Anellated pyridine compounds

ABSTRACT

The present invention is concerned with novel dual modulators of the 5-HT 2A  and D 3  receptors of formula (I) 
                         
wherein X, Y, A, R 1 , R 2 , and R 3  are as described herein, as well as pharmaceutically acceptable salts and esters thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as therapeutics.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.10166652.7, filed Jun. 21, 2010, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

In particular schizophrenia is characterized by complex symptomatologyincluding positive symptoms, (i.e. delusions and hallucinations), andnegative symptoms, (i.e. anhedonia, restricted fluency and productivityof thought and speech). In addition it is now well recognized thatcognitive impairment is the third major diagnostic category ofschizophrenia, characterized by loss in working memory as well as otherdeficits. Other symptoms include aggressiveness, depression and anxiety(Stahl, S. M., Essential Psychopharmacology. Neuroscientific Basis andPractical Applications (2000) 2^(nd) edition, Cambridge UniversityPress, Cambridge, UK).

Dopamine, a major catecholamine neurotransmitter, is involved in theregulation of a variety of functions which include emotion, cognition,motor functions, and positive reinforcement. The biological activitiesof dopamine are mediated through G protein-coupled receptors (GPCRs) andin human, five different dopamine receptors D₁-D₅ have been identified,where the D₂-like receptors (D₂, D₃ and D₄) couple to the G-proteinG_(αI). The D₃ dopamine receptor is most highly expressed in the nucleusaccumbens and is proposed to modulate the mesolimbic pathway consistingof neuronal projections from the ventral tegmental area, hippocampus andamygdala to the nucleus accumbens, which projects to the prefrontal andcingulate cortices as well as various thalamic nuclei. The limbiccircuit is thought to be important for emotional behavior and thus D₃receptor antagonists are proposed to modulate psychotic symptoms such ashallucinations, delusions and thought disorder (Joyce J. N., Millan M.J., Drug Discovery Today (2005) 10:917-925). In addition, it has beenreported that drug naive schizophrenic patients show altered levels ofD₃ receptor expression (Gurevich E. V. et al., Arch. Gen. Psychiatry(1997) 54, 225-232) and dopamine release (Laruelle M, Presentation atInstitut de Recherches Internationales Servier Workshop onSchizophrenia: Pathological Bases and Mechanisms of AntipsychoticAction, Chicago, Ill., 2000), indicating that a disturbed homeostasis ofdopamine plays an important role in the etiology of schizophrenicsymptoms.

The neurotransmitter serotonin (5-Hydroxytryptamine; 5-HT) is implicatedin several psychiatric conditions including schizophrenia (Kandel E. R.et al. (eds.), Principles of Neural Science (2000) 3^(rd) edition,Appleton & Lange, Norwalk, Conn.). The involvement of serotonin inpsychotic disorders is suggested by multiple studies which includetreatment in humans with the psychotropic drug Lysergic acid (LSD; aserotonin agonist) which can induce schizophrenia-like symptoms such ashallucinations (Leikin J. B. et al., Med. Toxicol. Adverse Drug Exp.(1989) 4:324-350). Furthermore, altered brain distribution of serotoninreceptors as well as an altered serotonergic tone, have been detected inschizophrenic patients (Harrison P. J., Br. J. Psychiatry Suppl. (1999)38:12-22).

In mammals, serotonin exerts its biological activities through a familyof 14 5-HT GPCRs. The 5-HT_(2A) receptor is most prominently expressedin the prefrontal cortex and at lower levels in the basal ganglia andthe hippocampus in human brain, and is coupled predominantly to theG-protein Gαq. Genetic linkage studies of a 5-HT_(2A) polymorph toschizophrenia (Spurlock G. et al., Mol. Psychiatry. (1998) 3:42-49), aswell as responsiveness to antipsychotic drugs (Arran, M. J. et al.,Lancet (2000) 355:1615-1616), further suggest a role for the 5-HT_(2A)receptor both in the treatment and pathology of psychosis. In addition,dopaminergic neurotransmission appears to be under the afferentregulation of the 5-HT_(2A) receptor (Porras G. et al.,Neuropsychopharmacology (2002) 26:311-324). Overall 5-HT_(2A) receptorantagonists are proposed to be suitable for the treatment of disordersassociated with dysfunctional dopaminergic systems. Moreover, 5-HT_(2A)receptor antagonism has been recognized as beneficial for the treatmentof psychosis (de Angelis L., Curr. Opin. Investig. Drugs (2002)3:106-112).

The D₃ and 5-HT_(2A) receptors besides the mentioned psychotic disordersare further reported to be linked to other psychoses including paranoiaand delusions (Reavill C. et al., JPET (2000) 294:1154-1165; Harrison P.J., Br. J. Psychiatry Suppl. (1999) 38:12-22), to drug dependency, abuseand withdrawal (Voxel S. R. et al., J. Neurosci. (2002) 22:9595-9603;Campos A. C. et al., Soc. Neurosci. Abstr., (2003) 322:8; Ashby C. R. etal., Synapse (2003) 48:154-156), attention deficit hyperactivitydisorders (ADHD) (Retz W. et al., J. Neural. Transm. (2003) 110:531-572;Levitan R. D. et al., J. Affective Disorder (2002) 71:229-233), as wellas to anxiety and depression (Reavill C. et al., JPET (2000)294:1154-1165; Drescher K. et al. Am. Soc. Neurosci. (2002) 894:6).

Currently used medications to treat schizophrenia, bipolar mania andother psychoses, include both typical (D₂/D₃ preferring) or the morerecent atypicals, which exhibit polypharmacology interacting at multiplereceptors (e.g., D₁, D₂, D₃, D₄, 5-HT_(1A), 5-HT_(2A), 5-HT_(2c), H₁,M₁, M₂, M₄, etc.)(Roth B. L. et al., Nat. Rev. Drug Discov. (2004)3:353-359). These antipsychotics, although relatively successful (somepatients exhibit treatment resistance) at treating the positive symptomsof schizophrenia, are less effective at treating negative symptoms,cognitive deficits, and associated depression and anxiety, all of whichlead to reduced patient quality of life and socioeconomic problems.Furthermore, patient compliance is compromised by prevalent side effectssuch as weight gain, extrapyramidal symptoms (EPS), and cardiovasculareffects (Lieberman J. A. et al., N. Engl. J. Med. (2005) 353:1209-1223).

Antipsychotic drug treatment has frequently been complicated by seriousside effects of widespread D₂ antagonism, notably an extrapyramidal orparkinsonian syndrome caused by antagonism of the dopaminergicprojection from substantia nigra to corpus striatum. D₂ receptorblockade induces catalepsy and has been associated with negative effectsagainst cognition. Also preferential blockade of D₃ vs. D₂ receptors,preserves and/or enhances cognitive function, and increasesfrontocortical cholinergic transmission. (Joyce J. N., Millan M J., DrugDiscovery Today (2005) 10:917-925, Moore N. A. et al., European Journalof Pharmacology (1993) 237:1-7; Barth V. N., Typical and atypicalantipsychotics: Relationships between rat in vivo dopamine D(2) receptoroccupancy assessed using LC/MS and changes in neurochemistry andcatalepsy. Dissertation Indiana University (2006); Millan M. J. et al.,Fr. Journal of Pharmacology and Experimental Therapeutics (2008)324:1212-1226; Wiecki T. V. et al., Psychopharmacology (2009)204:265-277).

The typical antipsychotic agents on the market today display D₂antagonism, and most have extrapyramidal side effects (EPS) such aspseudoparkinsonism and tardive dyskinesia (Howard H. R., Seeger T. F.,Annual Reports in Medicinal Chemistry (1993) 28:39). It has been shownby selective binding experiments that D₂ receptors are more concentratedin the striatal regions of the brain, which are responsible forlocomotor control than in the limbic regions which are responsible forthought processes. D₃ receptors are more concentrated in the limbic thanin the striatal regions. It is therefore believed that selective D₃ligands may relieve symptoms of schizophrenia without causing the EPSassociated with blockade of D₂ receptors (Gackenheimer S. L. et al., J.Pharmacol. Exp. Ther. (1995) 274:1558, Belliotti T. R., Bioorg. Med.Chem. Lett. (1997) 7:2403).

SUMMARY OF THE INVENTION

The present invention provides dual modulators of the 5-HT_(2A) and D₃receptors, their manufacture, pharmaceutical compositions comprisingthem and their use as therapeutics.

In particular, the present invention provides compounds of formula (I)

wherein

-   X is O or S;-   Y is —C(O)— or —S(O)₂—;-   A is a single bond or double bond,    -   with the proviso that when X is S then A is a double bond;-   R¹ is hydrogen, C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₂₋₇    alkynyl, cycloalkyl, heterocycloalkyl, aryl, aryl annellated to    heterocycloalkyl, heteroaryl, or —N(R⁶)₂, wherein C₁₋₇ alkyl, C₁₋₇    haloalkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl are optionally substituted by    one to three substituents selected independently from the group    consisting of cyano, cycloalkyl, heterocycloalkyl, aryl, aryl    annellated to heterocycloalkyl, heteroaryl, —C(O)N(R⁶)₂, —N(R⁶)₂,    —NH(CO)—C₁₋₇ alkyl, hydroxy, C₁₋₇ alkoxy, C₁₋₇ haloalkoxy, oxo, and    —S(O)₂R⁷, and wherein cycloalkyl, heterocycloalkyl, aryl, aryl    annellated to heterocycloalkyl and heteroaryl are optionally    substituted by one to three independent R⁴;-   R² and R³ are each independently hydrogen, halogen, C₁₋₇ alkyl, C₁₋₇    haloalkyl, hydroxy, C₁₋₇ alkoxy or C₁₋₇ haloalkoxy;-   R⁴ is halogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, cycloalkyl,    heterocycloalkyl, aryl, aryl annellated to heterocycloalkyl,    heteroaryl, —C(O)N(R⁶)₂, —N(R⁶)₂, —NH(CO)—C₁₋₇ alkyl, hydroxy, C₁₋₇    alkoxy, C₁₋₇ haloalkoxy, oxo, —S(O)₂R⁷, or C₁₋₇ alkyl substituted by    one to three substituents selected independently from the group    consisting of cyano, hydroxy, C₁₋₇ alkoxy, and C₁₋₇ haloalkoxy,    wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are    optionally substituted by one to three independent R⁵;-   R⁵ is halogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, hydroxy, C₁₋₇    alkoxy, C₁₋₇ haloalkoxy, or oxo;-   R⁶ is hydrogen or C₁₋₇ alkyl; and-   R⁷ is hydrogen, C₁₋₇ alkyl, or aryl, wherein aryl is optionally    substituted by one to three independent R⁵;    and pharmaceutically acceptable salts and esters thereof.

The compounds of the invention and their pharmaceutically acceptablesalts have high affinity and selectivity for both, the dopamine D₃ andserotonin 5-HT_(2A) receptors and are effective, alone or in combinationwith other drugs, in the treatment or prevention of psychotic disorders,as well as other diseases such as depression, anxiety, drug addiction,attention deficit hyperactivity disorders, dementia and memoryimpairment, while exhibiting fewer associated side effects. Psychoticdisorders encompass a variety of diseases, which include schizophrenia,positive, negative and/or cognitive symptoms associated withschizophrenia, schizoaffective disorders, bipolar disease, mania,psychotic depression, and other psychoses involving paranoia anddelusions.

The current invention provides compounds with high affinity and improvedselectivity for D₃ and 5-HT_(2A) receptors as well as methods for thetreatment of psychoses and other diseases, with fewer associated sideaffects. The compounds of the invention are dual modulators of the5-HT_(2A) and D₃ receptors and are selective at the D₂ receptor.

DETAILED DESCRIPTION OF THE INVENTION

The definitions described herein apply irrespective of whether the termsin question appear alone or in combination. It is contemplated that thedefinitions described herein may be appended to form chemically-relevantcombinations, such as “heterocycloalkyl-aryl,” “aryl-C₁₋₇alkyl-heterocycloalkyl,” “C₁₋₇ alkoxy-C₁₋₇ alkyl,” and the like.

The singular forms “a”, “an,” and “the” include plural referents unlessthe context clearly dictates otherwise, e.g. a compound refers to one ormore compounds or at least one compound.

The term “substituted” denotes that a specified group or moiety can bear1, 2, 3, 4, 5 or 6 substituents. Where any group can carry multiplesubstituents and a variety of possible substituents is provided, thesubstituents are independently selected and need not to be the same.When indicating the number of substituents, the term “one or more”refers to the range from one substituent to the highest possible numberof substitution, i.e. replacement of one hydrogen up to replacement ofall hydrogens by substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents, independently chosen from the group consisting ofpossible substituents.

The term “optional” or “optionally” denotes that a subsequentlydescribed event or circumstance can, but need not, occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “optional bond” meansthat the bond may or may not be present, and that the descriptionincludes single, double, or triple bonds.

The term “as defined above” and “as defined herein” when referring to avariable incorporates by reference the broad definition of the variableas well as particular, preferred, more preferred and most preferreddefinitions, if any.

Particular groups for the chemical groups whose definitions are givenherein are those specifically exemplified herein.

The nomenclature used in this Application is based on AutoNom 2000™, aSymyx Solutions Inc. computerized system for the generation of IUPACsystematic nomenclature.

Chemical structures shown herein were prepared using ISIS/Draw version2.5. Any open valency appearing on a carbon, oxygen, sulfur or nitrogenatom in the structures herein indicates the presence of a hydrogen.

The term “compound(s) of this invention” and “compound(s) of the presentinvention” refers to compounds of formula (I) and stereoisomers,tautomers, solvates, metabolites, salts (e.g., pharmaceuticallyacceptable salts), polymorphs and prodrugs thereof.

It will be appreciated, that the compounds of present invention can bederivatized at functional groups to provide derivatives which arecapable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of present invention invivo are also within the scope of this invention.

The term “pharmaceutically acceptable salt” denotes those salts whichretain the biological effectiveness and properties of the free bases andwhich are not biologically or otherwise undesirable, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, carbonic acid, phosphoric acid and the like, andorganic acids can be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic, and sulfonic classes of organicacids such as formic acid, acetic acid, propionic acid, glycolic acid,gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like. Particularembodiments of this invention are hydrochloride salts.

The term “pharmaceutically acceptable esters” denotes derivatives of thecompounds of present invention in which hydroxy groups have beenconverted to the corresponding esters with inorganic or organic acidssuch as nitric acid, sulphuric acid, phosphoric acid, citric acid,formic acid, maleic acid, acetic acid, succinic acid, tartaric acid,methanesulphonic acid, p-toluenesulphonic acid and the like, which arenon toxic to living organisms.

The terms “therapeutically inert carrier” and pharmaceuticallyacceptable excipient” denote any ingredient having no therapeuticactivity and being non-toxic such as disintegrators, binders, fillers,solvents, buffers, tonicity agents, stabilizers, antioxidants,surfactants or lubricants used in formulating pharmaceutical products.

The term “therapeutically effective amount” denotes an amount of acompound of the present invention that, when administered to a subject,(i) treats or prevents the particular disease, condition or disorder,(ii) attenuates, ameliorates or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, conditionor disorder described herein. The therapeutically effective amount willvary depending on the compound, disease state being treated, theseverity or the disease treated, the age and relative health of thesubject, the route and form of administration, the judgment of theattending medical or veterinary practitioner, and other factors.

Compounds of present invention can have one or more asymmetric carbonatoms and can exist in the form of optically pure enantiomers, mixturesof enantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbens or eluant). The invention embraces all of theseforms.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York,1994.

The term “halogen,” “halo,” and “halide” are used interchangeably hereinand denote fluoro, chloro, bromo, or iodo. Particular examples ofhalogen are fluoro and chloro, particularly fluoro.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 20 carbon atoms, in particular 1 to 12 carbonatoms. Furthermore, C₁₋₇ alkyl groups as described herein are particularalkyl groups.

The term “C₁₋₇ alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 7 carbon atoms, in particular 1 to 4 carbonatoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, tert-butyl and the like. Particular examples ofC₁₋₇ alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, iso-pentyl, and tert-pentyl, particularly methyl, ethyl andiso-propyl.

The term “C₁₋₇ haloalkyl” denotes a C₁₋₇ alkyl group as defined abovewherein at least one of the hydrogen atoms of the C₁₋₇ alkyl group hasbeen replaced by the same or different halogen atoms, in particular byfluoro. Examples of C₁₋₇ haloalkyl include but are not limited tomonofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, forexample 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,fluoromethyl, or trifluoromethyl, as well as those groups specificallyillustrated by the examples herein below. Particular examples of C₁₋₇haloalkyl are trifluoro-methyl, trifluoro-ethyl, and trifluoro n-propyl,most particularly trifluoro-ethyl.

The term “C₂₋₇ alkenyl” denotes a straight- or branched-hydrocarbonchain of 2 to 7, in particular 2 to 4, carbon atoms with at least onedouble bond. Examples of C₂₋₇ alkenyl include, but are not limited to,ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, i-butenyl,t-butenyl and the like. Particular examples of C₂₋₇ alkenyl are(E)-butenyl, and iso-butenyl, most particularly (E)-butenyl.

The term “C₂₋₇ alkynyl” denotes a straight- or branched hydrocarbonchain of 2 to 7 carbon atoms, in particular from 2 to 4 carbon atoms,and comprising one, two or three triple bonds. Examples of C₂₋₇ alkynylinclude, but are not limited to, ethynyl, propynyl, prop-1-ynyl,prop-2-ynyl, isopropynyl, n-butynyl, i-butynyl, t-butynyl and the like.Particular example of C₂₋₇ alkynyl is pronynyl, most particularlyprop-1-ynyl,

The term “C₁₋₇ alkoxy” denotes a moiety of the formula —O—R, wherein Ris a C₁₋₇ alkyl moiety as defined herein. Examples of C₁₋₇ alkoxymoieties include, but are not limited to, methoxy, ethoxy, isopropoxy,tert-butoxy and the like. Particular examples of C₁₋₇ alkoxy aremethoxy, ethoxy, and tert-butoxy, most particularly methoxy.

The term “C₁₋₇ haloalkoxy” denotes a C₁₋₇ alkoxy group as defined abovewherein at least one of the hydrogen atoms of the C₁₋₇ alkoxy group hasbeen replaced by the same or different halogen atoms, in particular byfluoro. Examples of C₁₋₇ haloalkoxy include but are not limited tomonofluoro-, difluoro- or trifluoro-methoxy, -ethoxy or -propoxy, forexample 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy,fluoromethoxy, or trifluoromethoxy, as well as those groups specificallyillustrated by the examples herein below.

The term “cycloalkyl” denotes a monovalent saturated monocyclic orbicyclic hydrocarbon radical of 3 to 8 ring carbon atoms. Bicyclic meansconsisting of two saturated carbocycles having two carbon atoms incommon, i.e. the bridge separating the two rings is either a single bondor a chain of one or two carbon atoms. Examples for monocycliccycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl orcycloheptyl. Examples for bicyclic cycloalkyl arebicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl or adamantanyl. Particularexamples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl, particularly cyclopropyl and cyclobutyl.

The term “heterocycloalkyl” denotes a monovalent saturated or partlyunsaturated mono- or bicyclic ring system of 4 to 9 ring atoms,comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, theremaining ring atoms being carbon. Bicyclic means consisting of twosaturated cycles having two ring atoms in common, i.e. the bridgeseparating the two rings is either a single bond or a chain of one ortwo ring atoms. Heterocycloalkyl can be unsubstituted or substituted asdescribed herein. Examples for monocyclic saturated heterocycloalkyl areazetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl,azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples forbicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl,quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturatedheterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl,tetrahydro-pyridinyl, or dihydropyranyl. Particular examples ofheterocycloalkyl are oxetanyl, piperidinyl, piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl anddioxanyl, most particularly dioxanyl, and tetrahydrofuranyl.

The term “aryl” denotes a monovalent aromatic carbocyclic mono- orbicyclic ring system comprising 6 to 10 carbon ring atoms. The arylgroup can optionally be substituted with one, two or three substituents,wherein each substituent is independently e.g. C₁₋₇ alkyl, halo, C₁₋₇alkoxy, sulfonyl, cyano, cycloalkyl, heterocyclyl, phenyl, unlessotherwise specifically indicated. Examples of aryl moieties includeoptionally substituted phenyl and optionally substituted naphthyl.Particular example of aryl is phenyl.

The term “aryl annellated to heterocycloalkyl” denotes an aryl asdefined herein and a heterocycloalkyl as defined herein which are fusedtogether sharing two adjacent ring atoms. Examples of aryl annellated toheterocycloalkyl include optionally substituted benzodioxolyl.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. The heteroaryl group can optionally be substituted as describedherein. Examples of heteroaryl moieties include optionally substitutedpyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl,pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl,benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl,isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl,benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, carbazolyl, or acridinyl. Particular example of heteroarylis isoxazolyl, benzoisoxazolyl, pyrrolyl, pyrazolyl, oxadiazolyl,pyridinyl, thienyl, pyrazinyl, or quinolinyl, most particularlyisoxazolyl, benzoisoxazolyl, thienyl, or quinolinyl.

The term “oxo” denotes a divalent oxygen radical atom, e.g. ═O.

The term “amino-protecting group” denotes groups intended to protect anamino group against undesirable reactions during synthetic proceduresand includes, but is not limited to, benzyl, benzyloxycarbonyl(carbobenzyloxy, CBZ), Fmoc (9-Fluorenylmethyloxycarbonyl),p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like. Furtherexamples of these groups are found in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, 2nd ed., John Wiley & Sons,Inc., New York, N.Y., 1991, chapter 7; E. Haslam, “Protective Groups inOrganic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,1973, Chapter 5, and T. W. Greene, “Protective Groups in OrganicSynthesis”, John Wiley and Sons, New York, N.Y., 1981. The term“protected amino group” refers to an amino group substituted with one ofthe above amino-protecting groups.

In detail, the present invention relates to compounds of formula (I)

wherein

-   X is O or S;-   Y is —C(O)— or —S(O)₂—;-   A is a single bond or double bond,    -   with the proviso that when X is S then A is a double bond;-   R¹ is hydrogen, C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₂₋₇    alkynyl, cycloalkyl, heterocycloalkyl, aryl, aryl annellated to    heterocycloalkyl, heteroaryl, or —N(R⁶)₂, wherein C₁₋₇ alkyl, C₁₋₇    haloalkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl are optionally substituted by    one to three substituents selected independently from the group    consisting of cyano, cycloalkyl, heterocycloalkyl, aryl, aryl    annellated to heterocycloalkyl, heteroaryl, —C(O)N(R⁶)₂, —N(R⁶)₂,    —NH(CO)—C₁₋₇ alkyl, hydroxy, C₁₋₇ alkoxy, C₁₋₇ haloalkoxy, oxo, and    —S(O)₂R⁷, and wherein cycloalkyl, heterocycloalkyl, aryl, aryl    annellated to heterocycloalkyl, and heteroaryl are optionally    substituted by one to three independent R⁴;-   R² and R³ are each independently hydrogen, halogen, C₁₋₇ alkyl, C₁₋₇    haloalkyl, hydroxy, C₁₋₇ alkoxy or C₁₋₇ haloalkoxy;-   R⁴ is halogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C(O)N(R⁶)₂, —N(R⁶)₂,    —NH(CO)—C₁₋₇ alkyl, hydroxy, C₁₋₇ alkoxy, C₁₋₇ haloalkoxy, oxo,    —S(O)₂R⁷, or C₁₋₇ alkyl substituted by one to three substituents    selected independently from the group consisting of cyano, hydroxy,    C₁₋₇ alkoxy, and C₁₋₇ haloalkoxy, wherein cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl are optionally substituted by    one to three independent R⁵;-   R⁵ is halogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, hydroxy, C₁₋₇    alkoxy, C₁₋₇ haloalkoxy, or oxo;-   R⁶ is hydrogen or C₁₋₇ alkyl; and-   R⁷ is hydrogen, C₁₋₇ alkyl, or aryl, wherein aryl is optionally    substituted by one to three independent R⁵;    and pharmaceutically acceptable salts and esters thereof.

Particular embodiments of present invention provide compounds of formula(I) and pharmaceutically acceptable salts thereof and pharmaceuticallyacceptable esters thereof.

Further, it is to be understood that every embodiment relating to aspecific residue X, Y, A R¹, R², R³, R⁴, R⁵, R⁶, or R⁷ as disclosedherein can be combined with any other embodiment relating to anotherresidue X, Y, A R¹, R², R³, R⁴, R⁵, R⁶, or R⁷ as disclosed herein.

In particular the present invention provides compounds of formula (I)wherein

-   X is O or S;-   Y is —C(O)— or —S(O)₂—;-   A is a single bond or double bond,    -   with the proviso that when X is S then A is a double bond;-   R¹ is hydrogen, C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₂₋₇    alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —N(R⁶)₂,    wherein C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl are    optionally substituted by one to three substituents selected    independently from the group consisting of cyano, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C(O)N(R⁶)₂, —N(R⁶)₂,    —NH(CO)—C₁₋₇ alkyl, hydroxy, C₁₋₇ alkoxy, C₁₋₇ haloalkoxy, oxo, and    —S(O)₂R⁷, and wherein cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl are optionally substituted by one to three independent    R⁴;-   R² and R³ are each independently hydrogen, halogen, C₁₋₇ alkyl, C₁₋₇    haloalkyl, hydroxy, C₁₋₇ alkoxy or C₁₋₇ haloalkoxy;-   R⁴ is halogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C(O)N(R⁶)₂, —N(R⁶)₂,    —NH(CO)—C₁₋₇ alkyl, hydroxy, C₁₋₇ alkoxy, C₁₋₇ haloalkoxy, oxo,    —S(O)₂R⁷, or C₁₋₇ alkyl substituted by one to three substituents    selected independently from the group consisting of cyano, hydroxy,    C₁₋₇ alkoxy, and C₁₋₇ haloalkoxy, wherein cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl are optionally substituted by    one to three independent R⁵;-   R⁵ is halogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, hydroxy, C₁₋₇    alkoxy, C₁₋₇ haloalkoxy, or oxo;-   R⁶ is hydrogen or C₁₋₇ alkyl; and-   R⁷ is hydrogen, C₁₋₇ alkyl, or aryl, wherein aryl is optionally    substituted by one to three independent R⁵;    and pharmaceutically acceptable salts and esters thereof.

In a particular embodiment of the compound of formula (I), X is O.

In a particular embodiment of the compound of formula (I), A is a singlebond.

In a particular embodiment of the compound of formula (I), A is a doublebond.

In a particular embodiment of the compound of formula (I), X is O and Ais a single bond.

In a particular embodiment of the compound of formula (I), X is O and Ais a double bond.

In a particular embodiment of the compound of formula (I), X is S and Ais a double bond.

In a particular embodiment of the compound of formula (I), Y is —C(O)—.

In a particular embodiment of the compound of formula (I), X is O, A isa single bond and Y is —C(O)—.

In a particular embodiment of the compound of formula (I), X is O, A isa double bond and Y is —C(O)—.

In a particular embodiment of the compound of formula (I), R¹ ishydrogen, C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,cycloalkyl, heterocycloalkyl, aryl, aryl annellated to heterocycloalkyl,heteroaryl, or —N(R⁶)₂, wherein C₁₋₇ alkyl, and C₁₋₇ haloalkyl areoptionally substituted by one to three substituents selectedindependently from the group consisting of cyano, cycloalkyl,heterocycloalkyl, aryl annellated to heterocycloalkyl, heteroaryl,—C(O)N(R⁶)₂, hydroxy, C₁₋₇ alkoxy, C₁₋₇ haloalkoxy, and —S(O)₂R⁷, andwherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl areoptionally substituted by one to three independent R⁴;

In a particular embodiment of the compound of formula (I), R¹ is C₁₋₇alkyl, C₁₋₇ haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,—N(R⁶)₂, or C₁₋₇ alkyl substituted by one to three substituents selectedindependently from the group consisting of cyano, cycloalkyl,heterocycloalkyl, hydroxy, C₁₋₇ alkoxy, and —S(O)₂R⁷, whereincycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionallysubstituted by one to three independent R⁴.

In a particular embodiment of the compound of formula (I), R¹ is—N(methyl)₂.

In a particular embodiment of the compound of formula (I), R¹ is methyl;methyl substituted by a substituent selected from the group consistingof cyano, cyclopropyl, cyclobutyl, hydroxy-cyclobutyl,methoxy-cyclopentyl, hydroxy-cyclohexyl, methoxy-cyclohexyl, oxetanyl,tetrahydrofuranyl, hydroxy-tetrahydrofuranyl, tetrahydropyranyl,dioxanyl, benzodioxolyl, methyl-isoxazolyl, benzoisoxazolyl, hydroxy,methoxy, ethoxy, and —S(O)₂-methyl; ethyl; ethyl substituted with asubstituent selected from the group consisting of hydroxy, methoxy, andC(O)—N(methyl)₂; n-propyl; n-propyl substituted by methoxy; iso-propyl;iso-propyl substituted by hydroxy; n-butyl; n-butyl substituted byhydroxy; iso-butyl; iso-butyl substituted by hydroxy; tert-butyl;iso-pentyl; tert-pentyl; trifluoro-methyl; trifluoro-ethyl;trifluoro-ethyl substituted by hydroxy; trifluoro-n-propyl;trifluoro-n-propyl substituted by hydroxy; (E)-butenyl; iso-butenyl;propynyl; cyclopropyl; cyclopropyl substituted by fluoro; cyclopropylsubstituted by hydroxy; cyclobutyl; cyclobutyl substituted by hydroxy;cyclohexyl; cyclohexyl substituted by methyl and hydroxy;tetrahydrofuranyl; tetrahydropyranyl; phenyl; phenyl substituted by asubstituent selected from the group consisting of fluoro, chloro, cyano,methyl, tert-butyl, tert-butoxy, piperidinyl, methyl-piperazinyl,morpholinyl, dioxo-thiomorpholinyl, phenyl, pyrrolyl, pyrazolyl,methyl-oxadiazolyl, and pyridinyl; benzodioxolyl; thienyl; thienylsubstituted by —S(O)₂-methyl; isoxazolyl; methyl-isoxazolyl; pyridinyl;methyl-pyridinyl; morpholinyl-pyridinyl; pyrazinyl;morpholinyl-pyrazinyl; or quinolinyl.

In a particular embodiment of the compound of formula (I), R¹ is methyl;methyl substituted with a substituent selected from the group consistingof cyano, cyclopropyl, cyclobutyl, methoxy-cyclopentyl,hydroxy-cyclohexyl, methoxy-cyclohexyl, hydroxy, methoxy, ethoxy,oxetanyl, tetrahydrofuranyl, hydroxy-tetrahydrofuranyl,tetrahydropyranyl, dioxanyl, methyl-isoxazolyl, benzoisoxazolyl and—S(O)₂-methyl; ethyl; ethyl substituted with a substituent selected fromthe group consisting of fluoro, hydroxy and methoxy; n-propyl,iso-propyl; n-butyl, n-butyl substituted by hydroxy, iso-butyl;tert-butyl; iso-pentyl, tert-pentyl; (E)-butenyl, propynyl, cyclopropyl;cyclopropyl substituted by fluoro; cyclopropyl substituted by hydroxy;cyclobutyl; cyclohexyl substituted by methyl and hydroxy;tetrahydrofuranyl; tetrahydropyranyl; phenyl; phenyl substituted with asubstituent selected from the group consisting of fluoro, chloro,trifluoro-methyl, morpholinyl, piperidinyl and phenyl; thienyl, thienylsubstituted by methylsulfonyl, or quinolinyl.

In a particular embodiment of the compound of formula (I), R¹ is methyl;methyl substituted with a substituent selected from the group consistingof cyano, cyclopropyl, cyclobutyl, methoxy-cyclopentyl,hydroxy-cyclohexyl, methoxy-cyclohexyl, hydroxy, methoxy, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl and —S(O)₂-methyl; ethyl;ethyl substituted with a substituent selected from the group consistingof fluoro, hydroxy and methoxy; iso-propyl; iso-butyl; tert-pentyl;cyclopropyl; cyclobutyl; tetrahydrofuranyl; tetrahydropyranyl; phenyl;phenyl substituted with a substituent selected from the group consistingof fluoro, morpholinyl and piperidinyl; or quinolinyl.

In a particular embodiment of the compound of formula (I), R¹ is methyl;methyl substituted with a substituent selected from the group consistingof cyano, cyclopropyl, hydroxy, dioxanyl and —S(O)₂-methyl; ethyl; ethylsubstituted with fluoro; iso-propyl, cyclopropyl; cyclobutyl; ortetrahydrofuranyl.

In a particular embodiment of the compound of formula (I), R² ishydrogen.

In a particular embodiment of the compound of formula (I), R³ ishydrogen or methyl.

In a particular embodiment of the compound of formula (I), R³ ishydrogen.

In a particular embodiment of the compound of formula (I), R⁴ ishalogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, cycloalkyl,heterocycloalkyl, hydroxy, C₁₋₇ alkoxy, aryl, aryl annellated toheterocycloalkyl, heteroaryl or —S(O)₂R⁷, wherein cycloalkyl,heterocycloalkyl, aryl, aryl annellated to heterocycloalkyl andheteroaryl, are optionally substituted by one to three independent R⁵.

In a particular embodiment of the compound of formula (I), R⁴ is fluoro,chloro, cyano, methyl, trifluoro-methyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopentyl substituted by methoxy, cyclohexyl substitutedby hydroxy or methoxy, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinylsubstituted by oxo, dioxanyl, phenyl, benzodioxolyl, pyrrolyl,pyrazolyl, oxadiazolyl, methyl-oxadiazolyl, pyridinyl, hydroxy, methoxy,ethoxy, tert-butoxy, or —S(O)₂-methyl.

In a particular embodiment of the compound of formula (I), R⁴ is fluoro,cyano, cyclopropyl, cyclobutyl, cyclopentyl substituted by methoxy,cyclohexyl substituted by hydroxy or methoxy, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl, hydroxy,methoxy, or —S(O)₂-methyl.

In a particular embodiment of the compound of formula (I), R⁴ is fluoro,morpholinyl, phenyl, or —S(O)₂-methyl.

In a particular embodiment of the compound of formula (I), R⁴ is fluoro,cyano, cyclopropyl, dioxanyl, hydroxy, or —S(O)₂-methyl.

In a particular embodiment of the compound of formula (I), R⁵ ishalogen, hydroxy, C₁₋₇ alkyl, C₁₋₇ alkoxy and oxo.

In a particular embodiment of the compound of formula (I), R⁵ is fluoro,hydroxy, methyl, methoxy, or oxo.

In a particular embodiment of the compound of formula (I), R⁶ is C₁₋₇alkyl.

In a particular embodiment of the compound of formula (I), R⁶ is methyl.

In a particular embodiment of the compound of formula (I), R⁷ is C₁₋₇alkyl.

In a particular embodiment of the compound of formula (I), R⁷ is methyl.

A particular embodiment of the present invention relates to compounds offormula (I) wherein the two opposing substituents at the centralcyclohexyl moiety of the molecular backbone, the amidyl residue and thepiperazinyl-ethyl residue, are oriented in trans-configuration.

A particular embodiment of the present invention relates to compounds offormula (I′)

wherein X, A, R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (I″)

wherein X, A, R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ia)

wherein Y, R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ia′)

wherein R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ia″)

wherein R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ib)

wherein Y, R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ib′)

wherein R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ib″)

wherein R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ic)

wherein Y, R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ic′)

wherein R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (Ic″)

wherein R¹, R² and R³ are as defined above.

A particular embodiment of the present invention relates to compounds offormula (I) as described in the examples as individual compounds as wellas pharmaceutically acceptable salts as well as pharmaceuticallyacceptable esters thereof. Furthermore, the substituents as found in thespecific examples described below, individually constitute separateparticular embodiments of the present invention.

Particular compounds of formula (I) of present invention are thoseselected from the group consisting of:

-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-3-methoxy-cyclopentyl)-acetamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-4-hydroxycyclohexyl)-acetamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxypropionamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-hydroxypropionamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxyacetamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxyacetamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-4-methoxy-cyclohexyl)-acetamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydropyran-4-yl)-acetamide;-   Tetrahydro-pyran-4-carboxylic acid    {trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;-   2-Ethoxy-N-{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   Cyclopropanecarboxylic acid    {trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide;-   N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   Ethanesulfonic acid    {trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;-   N′-(trans-4{[4-(furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}cyclohexyl)-N,N-dimethylsulfamide;-   N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;-   3-Methoxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;-   2-(trans-4-Methoxy-cyclohexyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-(trans-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-Methoxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-(Tetrahydro-pyran-4-yl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   Tetrahydro-pyran-4-carboxylic acid    {trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;-   2-((1R,3R)-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-((1S,3S)-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-Hydroxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-(trans-4-Hydroxy-cyclohexyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   Quinoline-4-carboxylic acid    {trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;-   N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide;-   Ethanesulfonic acid    {trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-tetrahydro-2H-pyran-4-carboxamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-2H-pyran-4-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methoxypropanamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(rac-1,4-dioxan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxyacetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methylsulfonyl-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-hydroxyacetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-hydroxypropanamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-3-carboxamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-2-carboxamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-fluoro-benzamide;-   trans-4-Chloro-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-trifluoromethyl-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide;-   Ethanesulfonic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-fluoro-benzenesulfonamide;-   trans-2-Cyclopropyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   Cyclobutanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   rac-Tetrahydro-pyran-3-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-4-Hydroxy-4-methyl-cyclohexanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   cis-4-Hydroxy-4-methyl-cyclohexanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide;-   1-Hydroxy-cyclopropanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-2-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-[1,4]dioxan-2-yl-acetamide;-   Quinoline-4-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   Cyclopropanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-rac-(tetrahydro-furan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-trans-(4-methoxy-cyclohexyl)-acetamide;-   N′-trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-N,N-dimethyl-sulfamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(S)-[1,4]dioxan-2-yl-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-(tetrahydro-furan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(S)-(tetrahydro-furan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2,2-dimethyl-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methyl-butyramide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethyl-butyramide;-   trans-2-Cyclobutyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-2,2-Difluoro-cyclopropanecarboxylic acid    (4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-isobutyramide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-2-methyl-butyramide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-oxetan-3-yl-acetamide;-   trans-3-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-1,1-dimethyl-urea;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2,2,2-trifluoro-acetamide;-   3-Methyl-but-2-enoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   (E)-Pent-3-enoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   But-2-ynoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-formamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(3-methyl-isoxazol-5-yl)-acetamide;-   3-Methyl-isoxazole-5-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-N′,N′-dimethyl-succinamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-3-methyl-butyramide;-   trans-(R)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4,4-trifluoro-3-hydroxy-butyramide;-   (S)-3-Hydroxy-pentanoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-((1S,3S)-3-methoxy-cyclopentyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-((S)-4-hydroxy-tetrahydro-furan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-butyramide;-   4-Methyl-pentanoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   Pentanoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4,4-trifluoro-butyramide;-   trans-N-(4-{2-[4-(6-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-Tetrahydro-pyran-4-carboxylic acid    (4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(6-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide;-   trans-3-Methoxy-N-(4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;-   trans-N-(4-{2-[4-(6-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide-   Tetrahydro-pyran-4-carboxylic acid    trans-(4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(6-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide;-   trans-3-Methoxy-N-(4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;-   trans-N-(4-{2-[4-(7-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-Tetrahydro-pyran-4-carboxylic acid    (4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(7-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide;-   trans-3-Methoxy-N-(4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;-   trans-N-(4-{2-[4-(7-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   Tetrahydro-pyran-4-carboxylic acid    trans-(4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(7-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide;-   trans-3-Methoxy-N-(4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;-   trans-(RS)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-2-hydroxy-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4-dimethoxy-butyramide;-   5-Methanesulfonyl-thiophene-2-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-6-methyl-nicotinamide;-   trans-4-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-(4-methyl-piperazin-1-yl)-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-6-morpholin-4-yl-nicotinamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyridin-3-yl-benzamide;-   Benzo[1,3]dioxole-5-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-2-Benzo[1,3]dioxol-5-yl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   1-Hydroxy-cyclobutanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-2-methyl-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-(1,2-dioxo-1λ6-thiomorpholin-4-yl)-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyrazol-1-yl-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzamide;-   Quinoline-6-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-2-Benzo[d]isoxazol-3-yl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   5-Morpholin-4-yl-pyrazine-2-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-4-tert-Butyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;-   trans-2,4-Dichloro-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyrrol-1-yl-benzamide;-   Biphenyl-4-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-(R)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-propionamide;-   trans-4-tert-Butoxy-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;-   trans-(S)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzenesulfonamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide;-   (R)-3-Hydroxy-pentanoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(1-hydroxy-cyclobutyl)-acetamide;    and    pharmaceutically acceptable salts and esters thereof.

Particular compounds of formula (I) of present invention are thoseselected from the group consisting of:

-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;-   N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-hydroxy-propionamide;-   N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;-   3-Methoxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;-   2-(trans-4-Methoxy-cyclohexyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-Methoxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-(Tetrahydro-pyran-4-yl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   Tetrahydro-pyran-4-carboxylic acid    {trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;-   2-((1R,3R)-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-((1S,3S)-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-Hydroxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   2-(trans-4-Hydroxy-cyclohexyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;-   N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide;-   Ethanesulfonic acid    {trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-2H-pyran-4-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methoxypropanamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(rac-1,4-dioxan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methylsulfonyl-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-hydroxyacetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-3-carboxamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-fluoro-benzamide;-   Ethanesulfonic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-2-Cyclopropyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   Cyclobutanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide;-   trans-2-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-[1,4]dioxan-2-yl-acetamide;-   Quinoline-4-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   Cyclopropanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-trans-(4-methoxy-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(S)-[1,4]dioxan-2-yl-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(S)-(tetrahydro-furan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methyl-butyramide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethyl-butyramide;-   trans-2-Cyclobutyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-isobutyramide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-2-methyl-butyramide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-oxetan-3-yl-acetamide;-   (E)-Pent-3-enoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   But-2-ynoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(3-methyl-isoxazol-5-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-3-methyl-butyramide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-((1S,3S)-3-methoxy-cyclopentyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-((S)-4-hydroxy-tetrahydro-furan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-butyramide;-   4-Methyl-pentanoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   Pentanoic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(7-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide;-   5-Methanesulfonyl-thiophene-2-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   Quinoline-6-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-2-Benzo[d]isoxazol-3-yl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   Biphenyl-4-carboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;    and    pharmaceutically acceptable salts and esters thereof.

Particular compounds of formula (I) of present invention are thoseselected from the group consisting of:

-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(rac-1,4-dioxan-2-yl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methylsulfonyl-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-hydroxyacetamide;-   trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-3-carboxamide;-   trans-2-Cyclopropyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   Cyclobutanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-2-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-propionamide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-[1,4]dioxan-2-yl-acetamide;-   Cyclopropanecarboxylic acid    trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;-   trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-isobutyramide;    and    pharmaceutically acceptable salts and esters thereof.

The invention further relates to a process for the manufacture ofcompounds of formula (I) as defined above. Compounds of formula (I) canbe prepared following standard methods comprising:

a) the reaction of a compound of formula (V)

with a compound of formula R¹C(O)OH, R¹C(O)OR or R¹S(O)₂Cl, wherein X,A, R¹, R² and R³ are as defined above and R is C₁₋₇ alkyl; orb) the reaction of a compound of formula (II)

with a compound of formula (VI)

wherein X, Y, A, R¹, R² and R³ are as defined above.

Particularly, compounds of formula (I) can be prepared followingstandard methods in accordance with Schemes 1 or 2.

According to Scheme 1, in a first step, a compound of formula (II) isreacted with an aldehyde of formula (III) under reductive aminationconditions such as for example the use of sodium triacetoxyborohydride(Na(AcO)₃BH) in a solvent such as 1,2-dichloroethane in the presence ofmethanol (MeOH) or an acid such as acetic acid (AcOH) to give a compoundof formula (IV). The amino moiety of aldehyde (III) is protected with anamino-protecting group such as a Boc moiety.

In a second step, compounds of formula (IV) are deprotected to givecompounds of formula (V). In such cases where the amino-protecting groupis a Boc functionality, compounds of formula (IV) can be reacted with anacid as for example HCl in an appropriate solvent mixture such asethylacetate (AcOEt) and MeOH to give primary amines isolated as the HClsalts (V).

Compounds of formula (V) can be reacted in a third step with a number ofdifferent nucleophiles to obtain compounds of formula (I). For instancereaction of compounds of formula (V) with a carboxylic acid of generalstructure R¹C(O)OH in the presence of a coupling agent such as0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and a base such as Hunig's base (N,N-Diisopropylethylamine,DIPEA) in a solvent such as dimethylformamide (DMF) leads to compoundsof formula (I′). In some instances carboxylic acids of general structureR¹C(O)OH or their salts can be prepared by saponification of an ester offormula R¹C(O)OR, wherein R is C₁₋₇ alkyl, with a reagent such as a baselike LiOH or mild reagents like potassium trimethylsilanolate (KOSiMe₃)in a solvent such as dichloromethane (DCM) followed by full evaporationof all solvent and direct use of the crude in the amide coupling stepdescribed above to obtain compounds of formula (I′). Yet in anotherinstance, compounds of formula (V) can be reacted with an appropriatereagent of general structure R¹S(O)₂Cl in the presence of a base such astriethylamine (Et₃N) in a solvent such as DCM to obtain compounds offormula (I″).

Derivatization at the primary amine does not necessarily need to becarried out in a last step, but can occur already prior to the reductiveamination step, thus avoiding the use of an amino-protecting group. Ascan be seen from Scheme 2, the reductive amination of a compound offormula (II) with an aldehyde of formula (VI′) under conditions wellknown to the person skilled in the art, will directly lead to an amideof formula (I′). An example for appropriate conditions for this step isthe use of Na(AcO)₃BH in a solvent such as 1,2-dichloroethane in thepresence or not of MeOH or an acid such as AcOH. Methods to generatecompounds of formula (VI′) have been described (e.g. WO 2007/093540).

In some occasions the starting materials (II) might need to besynthesized as they are not commercially available. For examplecompounds of formula (IIc) (Scheme 3) can be obtained from compounds offormula (IIa) by hydrogenation under conditions well known to the personskilled in the art. For instance a catalyst such as Pd/C can be used inpresence of an acid such as AcOH in a solvent such as MeOH. In otheroccasions an alternative reducing agent (like NaBH₄) could be usedparticularly in cases where R² and/or R³=halogen.

The corresponding salts compounds of formula (I) with acids can beobtained by standard methods known to the person skilled in the art,e.g. by dissolving the compound of formula (I) in a suitable solventsuch as e.g. dioxan or tetrahydrofuran (THF) and adding an appropriateamount of the corresponding acid. The products can usually be isolatedby filtration or by chromatography.

The conversion of compounds of formula (I) into pharmaceuticallyacceptable esters can be carried out e.g. by treatment of a suitablehydroxy-group present in the molecule with a suitable carboxylic acidusing e.g. a condensating reagent such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), N,N-dicylohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) orO-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluoroborate(TPTU).

Insofar as their preparation is not described in the examples, thecompounds of formula (I) as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth above. Starting materials are commercially available, known in theart or can be prepared by methods known in the art or in analogythereto.

The present invention also relates to compounds of formula (I) asdefined above, when prepared by a process as described above.

Another embodiment provides pharmaceutical compositions or medicamentscomprising the compounds of the invention and a therapeutically inertcarrier, diluent or pharmaceutically acceptable excipient, as well asmethods of using the compounds of the invention to prepare suchcompositions and medicaments.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

The compounds of the invention can be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention can be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions can comprise componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, preservatives, solubilizers, stabilizers, wetting agents,emulsifiers, sweeteners, colorants, flavorants, salts for varying theosmotic pressure, buffers, masking agents, antioxidants, and furtheractive agents. They can also comprise still other therapeuticallyvaluable substances.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel H. C. et al., Ansel's Pharmaceutical Dosage Forms andDrug Delivery Systems (2004) Lippincott, Williams & Wilkins,Philadelphia; Gennaro A. R. et al., Remington: The Science and Practiceof Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; andRowe R. C, Handbook of Pharmaceutical Excipients (2005) PharmaceuticalPress, Chicago. The formulations can also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents, diluents and other known additives to providean elegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 0.1 to 1000 mg per person of acompound of formula (I) should be appropriate, although the above upperlimit can also be exceeded when necessary.

An example of a suitable oral dosage form is a tablet comprising about100 mg to 500 mg of the compound of the invention compounded with about30 to 90 mg anhydrous lactose, about 5 to 40 mg sodium croscarmellose,about 5 to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment.

An example of an aerosol formulation can be prepared by dissolving thecompound, for example 10 to 100 mg, of the invention in a suitablebuffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. asalt such as sodium chloride, if desired. The solution can be filtered,e.g., using a 0.2 μm filter, to remove impurities and contaminants.

As described above, the novel compounds of the present invention andtheir pharmaceutically acceptable salts and esters possess valuablepharmacological properties and have been found to be dual modulators ofthe 5-HT_(2A) and D₃ receptors. The compounds of the present inventioncan therefore be used, either alone or in combination with other drugs,for the treatment or prevention of diseases which are modulated byligands of the 5-HT_(2A) or D₃ receptors. These diseases include, butare not limited to psychotic disorders, depression, anxiety, drugaddiction, attention deficit hyperactivity disorders, dementia andmemory impairment, wherein psychotic disorders include schizophrenia,positive, negative and/or cognitive symptoms associated withschizophrenia, schizoaffective disorders, bipolar disease, mania,psychotic depression, and other psychoses involving paranoia anddelusions.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptableexcipient.

The invention likewise embraces compounds as described above for use astherapeutically active substances, especially as therapeutically activesubstances for the treatment or prevention of diseases which are relatedto the 5-HT_(2A) or D₃ receptors, particularly for the treatment orprevention of psychotic disorders, depression, anxiety, drug addiction,attention deficit hyperactivity disorders, dementia and memoryimpairment, wherein psychotic disorders include schizophrenia, positive,negative and/or cognitive symptoms associated with schizophrenia,schizoaffective disorders, bipolar disease, mania, psychotic depression,and other psychoses involving paranoia and delusions.

In another embodiment, the invention relates to a method for thetreatment or prevention of diseases which are related to the 5-HT_(2A)or D₃ receptors, particularly for the treatment or prevention ofpsychotic disorders, depression, anxiety, drug addiction, attentiondeficit hyperactivity disorders, dementia and memory impairment, whereinpsychotic disorders include schizophrenia, positive, negative and/orcognitive symptoms associated with schizophrenia, schizoaffectivedisorders, bipolar disease, mania, psychotic depression, and otherpsychoses involving paranoia and delusions, which method comprisesadministering a compound as defined above to a human being or animal.

The invention also embraces the use of compounds as defined above forthe treatment or prevention of diseases which are related to the5-HT_(2A) or D₃ receptors, particularly for the treatment or preventionof psychotic disorders, depression, anxiety, drug addiction, attentiondeficit hyperactivity disorders, dementia and memory impairment, whereinpsychotic disorders include schizophrenia, positive, negative and/orcognitive symptoms associated with schizophrenia, schizoaffectivedisorders, bipolar disease, mania, psychotic depression, and otherpsychoses involving paranoia and delusions.

The invention also relates to the use of compounds as described abovefor the preparation of medicaments for the treatment or prevention ofdiseases which are related to the 5-HT_(2A) or D₃ receptors,particularly for the treatment or prevention of psychotic disorders,depression, anxiety, drug addiction, attention deficit hyperactivitydisorders, dementia and memory impairment, wherein psychotic disordersinclude schizophrenia, positive, negative and/or cognitive symptomsassociated with schizophrenia, schizoaffective disorders, bipolardisease, mania, psychotic depression, and other psychoses involvingparanoia and delusions. Such medicaments comprise a compound asdescribed above.

Particularly, compounds of present invention can be used in thetreatment or prevention of psychotic disorders including schizophreniaas well as positive, negative and/or cognitive symptoms associated withschizophrenia.

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

INTERMEDIATES Intermediate Atrans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride

Step A

trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester[CAS-Nr. 215790-29-7] (4.1 g, 17 mmol) was added to a solution under N₂of commercially available 4-piperazine-1-yl-furo[3,2-c]pyridine [CAS-Nr.81078-84-4] (3.1 g, 15 mmol) in 1,2-dichloroethane (40 ml) and MeOH (0.5ml). The resulting yellow solution was stirred 8 h at room temperaturebefore addition of Na(AcO)₃BH (4.9 g, 23 mmol). Stirring was continuedat room temperature for 18 h. The reaction mixture was poured on sat.aq. NaHCO₃ sol. (130 ml) and the product was extracted with EtOAc (3×100ml). The combined organic layers were washed with H₂O (130 ml) and brine(100 ml). After drying (MgSO₄) the solvent was evaporated and theproduct was purified by flash chromatography on silica gel (CH₂Cl₂/MeOH,100:0 to 95:5) to yieldtrans-{4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester as white crystals (3.4 g, 52%), MS (ISP) m/z=429.4[(M+H)⁺].

Step B

trans-{4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester (2.9 g, 7 mmol) was treated with 1 N HCl in EtOAc(100 ml, 100 mmol) and MeOH (1.9 ml) and the resulting mixture wasstirred over night at room temperature. A white precipitate was formedthat was collected by filtration and washed with EtOAc. The solid wasdried over night under high vacuum to yieldtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride as a white powder (2.9 g, 96%), MS (ISP) m/z=329.1[(M+H)⁺].

Intermediate Btrans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride

Step A

trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester[CAS-Nr. 215790-29-7] (1.0 g, 4 mmol) was added to a solution under N₂of commercially available 4-piperazine-1-yl-thieno[3,2-c]pyridine[CAS-Nr. 106261-27-2] (0.85 g, 4 mmol) in 1,2-dichloroethane (45 ml) andAcOH (0.22 ml, 4 mmol). The resulting reaction mixture was stirred 8 hat room temperature before addition of Na(AcO)₃BH (1.2 g, 6 mmol).Stirring was continued over night at room temperature. Sat. aq. NaHCO₃sol. was added and the product was extracted with EtOAc (2×). Thecombined organic layers were washed with H₂O and brine. After drying(MgSO₄) the solvent was evaporated and the product was purified by flashchromatography on silica gel (CH₂Cl₂/MeOH, 100:0 to 90:10) to yieldtrans-{4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester as a light yellow solid (1.2 g, 72%), MS (ISP)m/z=445.3 [(M+H)⁺].

Step B

{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester (1.2 g, 3 mmol) was treated with 1 N HCl in EtOAc(40 ml, 40 mmol) and MeOH (0.74 ml) and the resulting mixture wasstirred 4 h at room temperature. A white precipitate was formed that wascollected by filtration and washed with EtOAc. The solid was dried overnight under high vacuum to yieldtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride as a white powder (1.2 g, 94%), MS (ISP) m/z=345.1[(M+H)⁺].

Intermediate Ctrans-4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride

Step A

A mixture of commercially available4-(piperazin-1-yl)-furo[3,2-c]pyridine [CAS-No. 81078-84-4] (1 g, 4.92mmol), Pd/C 5% (0.46 g, 4.32 mmol), acetic acid (2.3 ml) in MeOH (6.9ml) was stirred in a hydrogen atmosphere at room temperature for 48 h.After removal of the catalyst by filtration the mixture was evaporated,the residue was dissolved in dichloromethane/MeOH/NH₄OH 80:10:1, washedwith 2N sodium carbonate solution, dried (MgSO₄) and evaporated. Thecrude material (0.68 g) was purified by chromatography on silica gel(dichloromethane/MeOH/NH₄OH 80:10:1) to yield4-(piperazin-1-yl)-2,3-dihydrofuro[3,2-c]pyridine as a white solid (0.39g, 39%), MS (ISP) m/z=206.2 [(M+H)⁺], mp 89.5° C.

Step B

To a solution of 4-(piperazin-1-yl)-2,3-dihydrofuro[3,2-c]pyridine (0.38g, 1.85 mmol) in dichloromethane (11 ml) and MeOH (0.3 ml) was added atroom temperature commercially availabletrans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (596 mg, 2.22 mmol)and triethylamine (375 mg, 516 μl, 3.7 mmol) and the solution wasallowed to stir for 30 min. Sodium triacetoxyboron hydride (706 mg, 3.33mmol) was added step wise and the mixture was allowed to stir for 16 hat room temperature. The solution was added to ice/2N sodium carbonatesolution (50 ml), extracted with dichloromethane (2×30 ml). The combinedorganic layers were dried (MgSO₄) and evaporated. The crude material(0.95 g) was purified by flash chromatography on silica gel (20% to 100%dichloromethane/dichloromethane-MeOH 9:1) to yieldtrans-tert-butyl-(4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylcarbamateas a white solid (0.49 g, 61.5%), MS (ISP) m/z=431.5 [(M+H)⁺], mp 89.5°C.

Step C

To a mixture oftrans-tert-butyl-(4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylcarbamate(0.49 g, 1.14 mmol) in dichloromethane (8 ml) was added at roomtemperature hydrochloric acid solution (4M in dioxane, 4.27 ml, 17.1mmol) and the mixture was allowed to stir for 3 h, the solvent wasevaporated, diethyl ether (20 ml) was added and the mixture was allowedto stir for 30 min at room temperature. The precipitate was collected byfiltration, washed with diethyl ether and dried to yield the titlecompound as a white solid (0.5 g, 100%), MS (ISP) m/z=331.3 [(M+H)⁺], mp287.5° C.

Intermediate Dtrans-4-{2-[4-(6-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride

The title compound, light yellow solid (1.39 g, 89%), MS (ISP) m/z=343.4[(M+H)⁺], mp 323.5° C., was prepared in accordance with the generalmethod of intermediate C, steps B and C, from6-methyl-4-(piperazin-1-yl)-furo[3,2-c]pyridine [CAS-No. 81078-82-2](0.75 g, 3.45 mmol) and commercially availabletrans-tert-butyl-4-(2-oxoethyl)-cyclohexyl-carbamate (1.0 g, 4.14 mmol).

Intermediate Etrans-4-{2-[4-(6-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride

Step A

Hydrogenation of 6-methyl-4-(piperazin-1-yl)-furo[3,2-c]pyridine[CAS-No. 81078-82-2] (0.86 g, 3.96 mmol) on 10% palladium on carbon (170mg, 1.6 mmol) according to general method of intermediate C, step Ayielded 6-methyl-4-(piperazin-1-yl)-2,3-dihydro-furo[3,2-c]pyridine aswhite solid (0.86 g, 99%), MS (ISP) m/z=220.3 [(M+H)⁺], mp 98° C.

Step B

The title compound, white solid (1.35 g, 76%), MS (ISP) m/z=345.2[(M+H)⁺], mp 293° C., was prepared in accordance with the general methodof intermediate C, steps B and C, from6-methyl-4-(piperazin-1-yl)-2,3-dihydro-furo[3,2-c]pyridine (step A)(0.86 g, 3.92 mmol) and commercially availabletrans-tert-butyl-4-(2-oxoethyl)-cyclohexyl-carbamate (1.14 g, 4.71mmol).

Intermediate Ftrans-4-{2-[4-(7-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl}-ethyl]-cyclohexylaminetrihydrochloride

Step A

A stirred mixture of commercially available4-chloro-7-methyl-furo[3,2-c]pyridine (2.5 g, 14.9 mmol), tert-butylpiperazine-1-carboxylate (3.33 g, 17.9 mmol), sodium tert.-butoxide(2.01 g, 20.9 mmol), palladium(II) acetate (335 mg, 1.49 mmol) and2-(di-tert.-butylphosphino) biphenyl (445 mg, 1.49 mmol) in toluene(33.0 ml) was heated for 16 h at 100° C. The mixture was cooled andwater (10 ml) was added. The mixture was extracted with ethylacetate(2×20 ml). The combined organic layers were washed with brine (20 ml),dried (MgSO4) and evaporated. The crude product (5.9 g) was furtherpurified by flash chromatography on silica gel (10% to 100% ethylacetate in heptane) to yield tert-butyl4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazine-1-carboxylate as ayellow solid (2.35 g, 50%), MS (ISP) m/z=318.3 [(M+H)⁺], mp 108.5° C.

Step B

A stirred solution of tert-butyl4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazine-1-carboxylate (step A)(2.34 g, 7.37 mmol) in dichloromethane (4.1 ml) was cooled to 0° C.,trifluoroacetic acid (8.41 g, 5.68 ml, 73.7 mmol) was added drop wiseand the reaction mixture was allowed to stir for 10 min at 0° C. and for30 min at room temperature. The solution was poured onto ice and 2Nsodium carbonate solution (50 ml) and extracted with dichloromethane(2×25 ml). The combined organic layers were washed with brine (30 mL),dried (MgSO4) and evaporated. The crude product (1.59 g) was furtherpurified by flash chromatography on silica gel (100%dichloromethane/MeOH/NH4OH 80:10:1) to yield7-methyl-4-(piperazin-1-yl)-furo[3,2-c]pyridine as a yellow solid (1.27g, 79%), MS (ISP) m/z=218.4 [(M+H)⁺], mp 111.5° C.

Step C

The title compound, light yellow solid (1.12 g, 91%), MS (ISP) m/z=343.4[(M+H)⁺], mp 314.5° C., was prepared in accordance with the generalmethod of intermediate C, steps B and C, from7-methyl-4-(piperazin-1-yl)-furo[3,2-c]pyridine (step B) (0.59 g, 2.72mmol) and commercially availabletrans-tert-butyl-4-(2-oxoethyl)-cyclohexyl-carbamate (925 mg, 3.26mmol).

Intermediate Gtrans-4-{2-[4-(7-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride

Step A

Hydrogenation of 7-methyl-4-(piperazin-1-yl)-furo[3,2-c]pyridine(intermediate F, step B) (0.68 g, 3.13 mmol) on 10% palladium on carbon(136 mg, 1.28 mmol) according to general method of intermediate C, stepA yielded 7-methyl-4-(piperazin-1-yl)-2,3-dihydro-furo[3,2-c]pyridine aswhite solid (0.64 g, 93%), MS (ISP) m/z=220.3 [(M+H)⁺], mp 114° C.

Step B

The title compound, white solid (0.55 g, 42%), MS (ISP) m/z=345.3[(M+H)⁺], mp 293° C., was prepared in accordance with the general methodof intermediate C, steps B and C, from7-methyl-4-(piperazin-1-yl)-2,3-dihydro-furo[3,2-c]pyridine (step A)(0.64 g, 2.92 mmol) and commercially availabletrans-tert-butyl-4-(2-oxoethyl)-cyclohexyl-carbamate (0.85 g, 3.52mmol).

EXAMPLES Example 1N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

To a solution under N₂ of commercially available4-piperazine-1-yl-furo[3,2-c]pyridine [CAS-Nr. 81078-84-4] (125 mg, 0.62mmol) in 1,2-dichloroethane (1.25 ml) were addedtrans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide [CAS-Nr. 946599-01-5, WO2007/093540] (124 mg, 0.68 mmol) and 3 drops of MeOH. The resultingyellow solution was stirred 18 h at room temperature before addition ofNa(AcO)₃BH (196 mg, 0.92 mmol). After stirring 18 h at room temperaturethe reaction mixture was partitioned between sat. aq. NaHCO₃ sol. (50ml) and EtOAc (50 ml). The aqueous layer was extracted with more EtOAc(2×25 ml). The combined organic layers were washed with H₂O (40 ml) andbrine (40 ml) and dried over MgSO₄. After evaporation of the solvent,the crude product (yellow crystals) was purified by flash chromatographyon silica gel (CH₂Cl₂/MeOH, 100:0 to 95:5) to yield the title compoundas light yellow crystals (95 mg, 42%), MS (ISP) m/z=371.2 [(M+H)⁺].

Example 2N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-3-methoxy-cyclopentyl)-acetamide

A mixture of racemic trans-(3-methoxy-cyclopentyl)-acetic acid methylester [WO 2009/019174] (70 mg, 0.41 mmol) and KOSiMe₃ (88 mg, 0.69 mmol)in CH₂Cl₂ (1.5 ml) was stirred at room temperature over night. Thesolvent was evaporated and DMF (1.5 ml) was added followed bytrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol), DIPEA (177 mg,1.37 mmol) and TBTU (143 mg, 0.44 mmol). After stirring 4 h at roomtemperature, sat. aq. NaHCO₃ sol. was added and the product wasextracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄), the solventwas evaporated and the crude product was purified by flashchromatography on silica gel (CH₂Cl₂/MeOH/25% NH_(3 aq) 140:10:1) toyield the title compound as a white solid (125 mg, 78%), MS (ISP)m/z=469.3 [(M+H)⁺].

Example 3N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-4-hydroxy-cyclohexyl)-acetamide

The title compound, white solid (159 mg, quant.), MS (ISP) m/z=469.3[(M+H)⁺], was prepared in analogy to example 2 fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) andtrans-(4-hydroxy-cyclohexyl)-acetic acid methyl ester [CAS-Nr.1124174-16-8, WO 2010/031735] (71 mg, 0.41 mmol). The purification wasperformed by precipitation from Et₂O.

Example 4N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide

To a solution in DMF (1.5 ml) oftrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) were addedpropionic acid (27 mg, 0.36 mmol), DIPEA (177 mg, 1.37 mmol) and TBTU(115 mg, 0.36 mmol). The reaction mixture was stirred over night at roomtemperature then sat. aq. NaHCO₃ sol. was added and the product wasextracted with EtOAc. After drying (Na₂SO₄) the solvent was evaporatedand the product was purified by flash chromatography on silica gel(CH₂Cl₂/MeOH/25% NH_(3 aq) 140:10:1) to yield the title compound as awhite solid (123 mg, 93%), MS (ISP) m/z=385.3 [(M+H)⁺].

Example 5N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxy-propionamide

The title compound, white solid (122 mg, 86%), MS (ISP) m/z=415.3[(M+H)⁺], was prepared following the method of example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) and3-methoxy-propionic acid (37 mg, 0.36 mmol).

Example 6N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-hydroxy-propionamide

The title compound, white solid (10 mg, 7%), MS (ISP) m/z=401.4[(M+H)⁺], was prepared following the method of example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) and3-hydroxy-propionic acid (32 mg, 0.36 mmol).

Example 7N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-acetamide

The title compound, white solid (98 mg, 75%), MS (ISP) m/z=387.2[(M+H)⁺], was prepared following the method of example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) and hydroxy-aceticacid (27 mg, 0.36 mmol).

Example 8N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide

The title compound, white solid (120 mg, 87%), MS (ISP) m/z=401.3[(M+H)⁺], was prepared following the method of example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) and methoxy-aceticacid (32 mg, 0.36 mmol).

Example 9N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-4-methoxy-cyclohexyl)-acetamide

The title compound, white solid (138 mg, 83%), MS (ISP) m/z=483.3[(M+H)⁺], was prepared following the method of example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) and(trans-4-methoxy-cyclohexyl)-acetic acid [CAS-Nr. 879877-61-9, US2010/075985] (62 mg, 0.36 mmol).

Example 10N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydro-pyran-4-yl)-acetamide

The title compound, white solid (116 mg, 75%), MS (ISP) m/z=455.3[(M+H)⁺], was prepared following the method of example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) and(tetrahydro-pyran-4-yl)-acetic acid (52 mg, 0.36 mmol).

Example 11

Tetrahydro-pyran-4-carboxylic acid{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white solid (123 mg, 82%), MS (ISP) m/z=441.4[(M+H)⁺], was prepared following the method of example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) andtetrahydro-pyran-4-carboxylic acid (47 mg, 0.36 mmol).

Example 122-Ethoxy-N-{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound, white crystals (86 mg, 60%), MS (ISP) m/z=415.3[(M+H)⁺], was prepared in analogy to example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) and ethoxyaceticacid (43 mg, 0.41 mmol).

Example 13 Cyclopropanecarboxylic acid{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white crystals (118 mg, 87%), MS (ISP) m/z=397.2[(M+H)⁺], was prepared in analogy to example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) andcyclopropanecarboxylic acid (41 mg, 0.47 mmol).

Example 14N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl}-cyclohexyl]-methanesulfonamide

trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) was dissolved inCH₂Cl₂ (1.5 ml) and the solution was cooled to 0° C. Et₃N (139 mg, 1.37mmol) and methanesulfonyl chloride (78 mg, 0.68 mmol) were added and thereaction mixture was stirred over night at room temperature. H₂O wasadded and the product was extracted with CH₂Cl₂. The organic layer wasdried (Na₂SO₄) and the solvent was evaporated. Purification by flashchromatography over silica gel (CH₂Cl₂/MeOH/25% NH_(3 aq) 140:10:1)yielded the title compound as a white solid (78 mg, 56%), MS (ISP)m/z=407.2 [(M+H)⁺].

Example 15N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound, light brown solid (114 mg, 43%), MS (ISP) m/z=387.1[(M+H)⁺], was prepared in analogy to example 1 from commerciallyavailable 4-piperazine-1-yl-thieno[3,2-c]pyridine [CAS-Nr. 106261-27-2](150 mg, 0.68 mmol) and trans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide[CAS-Nr. 946599-01-5, WO 2007/093540] (125 mg, 0.68 mmol). Purificationwas performed by flash chromatography over silica gel (CH₂Cl₂/MeOH/25%NH_(3 aq) 140:10:1).

Example 16 Ethanesulfonic acid{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, light brown foam (77 mg, 54%), MS (ISP) m/z=421.2[(M+H)⁺], was prepared in analogy to example 14 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) and ethanesulfonylchloride (88 mg, 0.68 mmol).

Example 17N′-(trans-4{[4-(furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}cyclohexyl)-N,N-dimethylsulfamide

trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) was dissolved inCH₂Cl₂ (1.5 ml) and the solution was cooled to 0° C. Et₃N (139 mg, 1.37mmol) and dimethylsulfamoylchloride (98 mg, 0.68 mmol) were added andthe reaction mixture was stirred over night at room temperature. H₂O wasadded and the product was extracted with CH₂Cl₂. The organic layer wasdried (Na₂SO₄) and the solvent was evaporated. Purification by flashchromatography over silica gel (CH₂Cl₂/MeOH/25% NH_(3 aq) 140:10:1)yielded the title compound as a white solid (89 mg, 60%), MS (ISP)m/z=436.3 [(M+H)⁺].

Example 18N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide

The title compound was prepared in analogy to example 4 starting fromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (100 mg, 0.22 mmol) and propionic acid(17 mg, 0.23 mmol). Purification by flash chromatography on silica gel(CH2Cl2/MeOH 95:5). White crystals (31 mg, 35%), MS (ISP) m/z=401.3[(M+H)⁺].

Example 193-Methoxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide

The title compound was prepared in analogy to example 4 starting fromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (100 mg, 0.22 mmol) and3-methoxypropionic acid (24 mg, 0.23 mmol). Purification by flashchromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (61 mg,64%), MS (ISP) m/z=431.3 [(M+H)⁺].

Example 202-(trans-4-Methoxy-cyclohexyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound was prepared in analogy to example 4 starting fromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (100 mg, 0.22 mmol) and(trans-4-methoxy-cyclohexyl)-acetic acid [CAS-Nr. 879877-61-9, US2010/075985] (40 mg, 0.23 mmol). Purification by flash chromatography onsilica gel (CH₂Cl₂/MeOH 95:5). White crystals (68 mg, 62%), MS (ISP)m/z=499.3 [(M+H)⁺].

Example 212-(trans-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound was prepared in analogy to example 2 starting fromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (100 mg, 0.22 mmol) and racemictrans-(3-methoxy-cyclopentyl)-acetic acid methyl ester [WO 2009/019174](46 mg, 0.27 mmol). Purification by flash chromatography on silica gel(CH₂Cl₂/MeOH 95:5). White crystals (61 mg, 57%), MS (ISP) m/z=485.4[(M+H)⁺].

Example 222-Methoxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound was prepared in analogy to example 4 starting fromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (150 mg, 0.33 mmol) and methoxyaceticacid (31 mg, 0.34 mmol). Purification by flash chromatography on silicagel (CH₂Cl₂/MeOH 95:5). White solid (66 mg, 48%), MS (ISP) m/z=417.1[(M+H)⁺].

Example 232-(Tetrahydro-pyran-4-yl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound was prepared in analogy to example 4 starting fromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (150 mg, 0.33 mmol) andtetrahydropyran-4-yl-acetic acid (50 mg, 0.35 mmol). Purification byflash chromatography on silica gel (CH₂Cl₂/MeOH 95:5). Off-whitecrystals (108 mg, 69%), MS (ISP) m/z=471.2 [(M+H)⁺].

Example 24 Tetrahydro-pyran-4-carboxylic acid{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound was prepared in analogy to example 4 starting fromtrans-4-[2-(4-thieno[3,2-e]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (150 mg, 0.33 mmol) andtetrahydropyran-4-ylcarboxylic acid (45 mg, 0.34 mmol). Purification byflash chromatography on silica gel (CH₂Cl₂/MeOH 95:5). White crystals(51 mg, 34%), MS (ISP) m/z=457.3 [(M+H)⁺].

Example 252-((1R,3R)-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

and Example 262-((1S,3S)-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

Racemic2-(trans-3-methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide(example 21) (50 mg, 0.10 mmol) was separated by HPLC into itsenantiomers. Chiralpak AD (5×50 cm) column, 20% iPrOH in heptane.(+)-Enantiomer (18 mg, 36%) Rt=94 min, MS (ISP) m/z=485.4 [(M+H)⁺].(−)-Enantiomer (17 mg, 34%) Rt=115 min, MS (ISP) m/z=485.4 [(M+H)⁺].

Example 272-Hydroxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound was prepared in analogy to example 4 starting fromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (150 mg, 0.33 mmol) and glycolic acid(26 mg, 0.34 mmol). Purification by flash chromatography on silica gel(CH₂Cl₂/MeOH 95:5). White solid (67 mg, 50%), MS (ISP) m/z=403.3[(M+H)⁺].

Example 282-(trans-4-Hydroxy-cyclohexyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide

The title compound was prepared in analogy to example 2 starting fromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B) (1150 mg, 0.33 mmol) andtrans-(4-hydroxy-cyclohexyl)-acetic acid methyl ester [CAS-Nr.1124174-16-8, WO 2010/031735] (68 mg, 0.39 mmol). Purification by flashchromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (83 mg,52%), MS (ISP) m/z=485.4 [(M+H)⁺].

Example 29

Quinoline-4-carboxylic acid{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, white crystals (70 mg, 42%), MS (ISP) m/z=484.4[(M+H)⁺], was prepared following the method of example 4 starting fromtrans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate A) (150 mg, 0.34 mmol) andquinoline-4-carboxylic acid (71 mg, 0.41 mmol). Purification by flashchromatography on silica gel (CH₂Cl₂/MeOH 95:5).

Example 30N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide

The title compound, off white solid (26 mg, 18%), MS (ISP) m/z=423.1[(M+H)⁺], was prepared following the procedure for example 14 startingfromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B (150 mg, 0.34 mmol) and methanesulfonylchloride (77 mg, 0.68 mmol).

Example 31 Ethanesulfonic acid{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide

The title compound, off white solid (41 mg, 28%), MS (ISP) m/z=437.2[(M+H)⁺], was prepared following the procedure for example 14 startingfromtrans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylaminetrihydrochloride (intermediate B (150 mg, 0.34 mmol) and ethanesulfonylchloride (87 mg, 0.68 mmol).

Example 32trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

To a stirred mixture oftrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) in DMF (1.8 ml)was added N,N-diisopropylethylamine (210 mg, 278 μl, 1.63 mmol), aceticacid (18.0 mg, 17.2 μl, 300 μmol) and TBTU (128 mg, 400 μmol). Themixture was allowed to stir at room temperature for 4 h. The mixture wasadded to ice/water (5 ml) and 1N NaOH (5 ml) and extracted withdichloromethane/MeOH (9:1, 20 ml). The organic phase was washed withbrine (20 ml), dried (MgSO₄) and evaporated. The crude material (0.15 g)was triturated with dichloromethane (2 ml) and diethyl ether (5 ml) for½ h, the precipitate was collected by filtration, washed with diethylether and dried to yield the title compound as off-white solid (92 mg,99%), MS (ISP) m/z=373.2 [(M+H)⁺], mp 260° C.

Example 33trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-tetrahydro-2H-pyran-4-carboxamide

The title compound, off-white solid (101 mg, 91%), MS (ISP) m/z=443.5[(M+H)⁺], mp 263° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andtetrahydropyran-4-yl-carboxylic acid.

Example 34trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-2H-pyran-4-yl)-acetamide

The title compound, off-white solid (105 mg, 92%), MS (ISP) m/z=457.4[(M+H)⁺], mp 233° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andtetrahydropyran-4-yl-acetic acid.

Example 35trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methoxypropanamide

The title compound, off-white solid (65 mg, 62%), MS (ISP) m/z=417.4[(M+H)⁺], mp 246.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and3-methoxypropionic acid.

Example 36trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide

The title compound, white solid (95 mg, 82%), MS (ISP) m/z=387.4[(M+H)⁺], mp 192.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (132 mg, 0.3 mmol) and propionic acid.

Example 37trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(rac-1,4-dioxan-2-yl)-acetamide

The title compound, white solid (107 mg, 78%), MS (ISP) m/z=459.4[(M+H)⁺], mp 186° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (132 mg, 0.3 mmol) andrac-(1,4-dioxan-2-yl)-acetic acid.

Example 38trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxyacetamide

The title compound, white solid (86 mg, 71%), MS (ISP) m/z=403.4[(M+H)⁺], mp 169.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (132 mg, 0.3 mmol) and methoxyaceticacid.

Example 39trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methylsulfonyl-acetamide

The title compound, off-white solid (106 mg, 78%), MS (ISP) m/z=451.3[(M+H)⁺], mp 260.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (132 mg, 0.3 mmol) and2-methylsulfonyl-acetic acid.

Example 40trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-hydroxyacetamide

The title compound, white solid (110 mg, 94%), MS (ISP) m/z=389.3[(M+H)⁺], mp 237° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (132 mg, 0.3 mmol) and hydroxyaceticacid.

Example 41trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-hydroxypropanamide

The title compound, white solid (80 mg, 66%), MS (ISP) m/z=403.4[(M+H)⁺], mp 173° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (132 mg, 0.3 mmol) and3-hydroxy-propionic acid

Example 42trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-3-carboxamide

The title compound, white solid (101 mg, 79%), MS (ISP) m/z=429.3[(M+H)⁺], mp 208.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (132 mg, 0.3 mmol) andrac-tetrahydrofuran-3-carboxylic acid.

Example 43trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-2-carboxamide

The title compound, white solid (100 mg, 78%), MS (ISP) m/z=429.3[(M+H)⁺], mp 176.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (132 mg, 0.3 mmol) andrac-tetrahydrofuran-2-carboxylic acid.

Example 44trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide

The title compound, white solid (100 mg, 92%), MS (ISP) m/z=435.3[(M+H)⁺], mp 207.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and benzoic acid.

Example 45trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-fluoro-benzamide

The title compound, white solid (100 mg, 88%), MS (ISP) m/z=453.3[(M+H)⁺], mp 209.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-fluorobenzoic acid.

Example 46trans-4-Chloro-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide

The title compound, off-white solid (103 mg, 88%), MS (ISP) m/z=469.3[(M+H)⁺], mp 226.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-chlorobenzoic acid.

Example 47trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-trifluoromethyl-benzamide

The title compound, off-white solid (111 mg, 88%), MS (ISP) m/z=503.3[(M+H)⁺], mp 227° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-trifluoromethyl-benzoic acid.

Example 48trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide

To a stirred mixture oftrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) in dichloromethane(1.6 ml) was added at room temperature triethylamine (139 mg, 192 μl,1.38 mmol) and methanesulfonyl chloride (43.0 mg, 29.2 μl, 375 μmol).The mixture was allowed to stir at room temperature for 4 h, poured intoice/water (5 ml) and 1N sodium hydroxide solution (5 ml) and extractedwith dichloromethane (2×20 ml). The combined organic layers were washedwith brine (20 ml), dried (MgSO₄) and evaporated. The crude material(0.1 g) was triturated with dichloromethane (1 ml) and heptane (5 mL)for 30 min. The precipitate was collected by filtration, washed withheptane and dried to yield the title compound as a white solid (90 mg,88%), MS (ISP) m/z=409.4 [(M+H)⁺], mp 220° C.

Example 49 Ethanesulfonic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (92 mg, 87%), MS (ISP) m/z=423.3[(M+H)⁺], mp 224° C., was prepared in accordance with the general methodof example 48 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and ethanesulfonylchloride.

Example 50trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-fluoro-benzenesulfonamide

The title compound, light yellow solid (109 mg, 89%), MS (ISP) m/z=489.4[(M+H)⁺], mp 221° C., was prepared in accordance with the general methodof example 48 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-fluoro-benzene-1-sulfonyl chloride.

Example 51trans-2-Cyclopropyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, white solid (86 mg, 83%), MS (ISP) m/z=413.5[(M+H)⁺], mp 193° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andcyclopropyl-acetic acid.

Example 52 Cyclobutanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (77 mg, 75%), MS (ISP) m/z=413.5[(M+H)⁺], mp 202° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andcyclobutanecarboxylic acid.

Example 53 rac-Tetrahydro-pyran-3-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (91 mg, 82%), MS (ISP) m/z=443.5[(M+H)⁺], mp 216° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andrac-tetrahydro-pyran-3-carboxylic acid.

Example 54 trans-4-Hydroxy-4-methyl-cyclohexanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, light brown solid (56 mg, 48%), MS (ISP) m/z=471.5[(M+H)⁺], mp 171° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andtrans-4-hydroxy-4-methyl-cyclohexanecarboxylic acid.

Example 55

cis-4-Hydroxy-4-methyl-cyclohexanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, off-white solid (79 mg, 67%), MS (ISP) m/z=471.5[(M+H)⁺], mp 216.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andcis-4-hydroxy-4-methyl-cyclohexanecarboxylic acid.

Example 56trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide

The title compound, off-white solid (100 mg, 77%), MS (ISP) m/z=518.5[(M+H)⁺], mp 214.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-piperidin-1-yl-benzoic acid.

Example 57trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide

The title compound, off-white solid (104 mg, 80%), MS (ISP) m/z=520.5[(M+H)⁺], mp 228.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-morpholin-4-yl-benzoic acid.

Example 58 1-Hydroxy-cyclopropanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, off-white solid (41 mg, 40%), MS (ISP) m/z=415.4[(M+H)⁺], mp 174.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and1-hydroxy-cyclopropanecarboxylic acid.

Example 59trans-2-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, off-white solid (86 mg, 87%), MS (ISP) m/z=398.3[(M+H)⁺], mp 188° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyano-aceticacid.

Example 60trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-propionamide

The title compound, white solid (89 mg, 81%), MS (ISP) m/z=441.3[(M+H)⁺], mp 195.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and3,3,3-trifluoro-propionic acid.

Example 61trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-[1,4]dioxan-2-yl-acetamide

The title compound, white solid (92 mg, 80%), MS (ISP) m/z=459.5[(M+H)⁺], mp 193.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and(R)-[1,4]dioxan-2-yl-acetic acid.

Example 62 Quinoline-4-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (104 mg, 86%), MS (ISP) m/z=486.5[(M+H)⁺], mp 210° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andquinoline-4-carboxylic acid.

Example 63 Cyclopropanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (86 mg, 86%), MS (ISP) m/z=399.3[(M+H)⁺], mp 213° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andcyclopropanecarboxylic acid.

Example 64trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-rac-(tetrahydro-furan-2-yl)-acetamide

The title compound, white solid (85 mg, 77%), MS (ISP) m/z=443.5[(M+H)⁺], mp 181.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andrac-(tetrahydro-furan-2-yl)-acetic acid.

Example 65trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-trans-(4-methoxy-cyclohexyl)-acetamide

The title compound, white solid (106 mg, 88%), MS (ISP) m/z=485.6[(M+H)⁺], mp 192.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andtrans-(4-methoxy-cyclohexyl)-acetic acid.

Example 66N′-trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-N,N-dimethyl-sulfamide

The title compound, light yellow solid (32 mg, 29%), MS (ISP) m/z=438.4[(M+H)⁺], mp 139.5° C., was prepared in accordance with the generalmethod of example 48 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andN,N-dimethylsulfamoyl chloride.

Example 67trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(S)-[1,4]dioxan-2-yl-acetamide

The title compound, white solid (107 mg, 93%), MS (ISP) m/z=459.5[(M+H)⁺], mp 192° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and(S)-[1,4]dioxan-2-yl-acetic acid.

Example 68trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-(tetrahydro-furan-2-yl)-acetamide

The title compound, white solid (87 mg, 79%), MS (ISP) m/z=443.5[(M+H)⁺], mp 183° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and(R)-(tetrahydro-furan-2-yl)-acetic acid.

Example 69trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(S)-(tetrahydro-furan-2-yl)-acetamide

The title compound, white solid (91 mg, 82%), MS (ISP) m/z=443.6[(M+H)⁺], mp 183.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and(S)-(tetrahydro-furan-2-yl)-acetic acid.

Example 70trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2,2-dimethyl-propionamide

The title compound, white solid (70 mg, 68%), MS (ISP) m/z=415.4[(M+H)⁺], mp 185° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and2,2-dimethyl-propionic acid.

Example 71trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methyl-butyramide

The title compound, white solid (84 mg, 81%), MS (ISP) m/z=415.4[(M+H)⁺], mp 202.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and3-methyl-butyric acid.

Example 72trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethyl-butyramide

The title compound, white solid (87 mg, 81%), MS (ISP) m/z=429.4[(M+H)⁺], mp 192.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and3,3-dimethyl-butyric acid.

Example 73trans-2-Cyclobutyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, white solid (81 mg, 76%), MS (ISP) m/z=427.5[(M+H)⁺], mp 193° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andcyclobutane-acetic acid.

Example 74 trans-2,2-Difluoro-cyclopropanecarboxylic acid(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (92 mg, 85%), MS (ISP) m/z=435.4[(M+H)⁺], mp 184.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and2,2-difluorocyclopropane-carboxylic acid.

Example 75trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-isobutyramide

The title compound, white solid (62 mg, 62%), MS (ISP) m/z=401.5[(M+H)⁺], mp 219° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and isobutyricacid.

Example 76trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-2-methyl-butyramide

The title compound, white solid (51 mg, 49%), MS (ISP) m/z=415.5[(M+H)⁺], mp 205.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andrac-2-methylbutanoic acid

Example 77trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-oxetan-3-yl-acetamide

The title compound, white solid (99 mg, 92%), MS (ISP) m/z=429.4[(M+H)⁺], mp 195° C., was prepared in accordance with the general methodof example 2 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl2-(oxetan-3-yl)acetate.

Example 78trans-3-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-1,1-dimethyl-urea

The title compound, white solid (90 mg, 90%), MS (ISP) m/z=402.5[(M+H)⁺], mp 260° C., was prepared in accordance with the general methodof example 48 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) anddimethylcarbamic chloride.

Example 79trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2,2,2-trifluoro-acetamide

The title compound, white solid (6.5 mg, 6%), MS (ISP) m/z=427.3[(M+H)⁺], mp 213° C., was prepared in accordance with the general methodof example 48 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and trifluoroacetic acid anhydride.

Example 80 3-Methyl-but-2-enoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, off-white solid (78 mg, 76%), MS (ISP) m/z=413.5[(M+H)⁺], mp 164.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and3-methyl-but-2-enoic acid.

Example 81

(E)-Pent-3-enoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (95 mg, 92%), MS (ISP) m/z=413.5[(M+H)⁺], mp 175.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and(E)-pent-3-enoic acid.

Example 82 But-2-ynoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (93 mg, 94%), MS (ISP) m/z=397.4[(M+H)⁺], mp 193° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and but-2-ynoicacid.

Example 83trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-formamide

The title compound, off-white solid (17 mg, 30%), MS (ISP) m/z=359.4[(M+H)⁺], mp 170.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (70.4 mg, 0.16 mmol) and formic acid.

Example 84trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(3-methyl-isoxazol-5-yl)-acetamide

The title compound, white solid (68 mg, 75%), MS (ISP) m/z=454.4[(M+H)⁺], mp 172.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and2-(3-methylisoxazol-5-yl)-acetic acid.

Example 85 3-Methyl-isoxazole-5-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, off-white solid (62 mg, 71%), MS (ISP) m/z=440.4[(M+H)⁺], mp 218° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and3-methylisoxazole-5-carboxylic acid.

Example 86trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-N′,N′-dimethyl-succinamide

The title compound, white solid (48 mg, 52%), MS (ISP) m/z=458.6[(M+H)⁺], mp 188° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and4-(dimethylamino)-4-oxobutanoic acid.

Example 87trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-3-methyl-butyramide

The title compound, off-white solid (68 mg, 79%), MS (ISP) m/z=431.6[(M+H)⁺], mp 208° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and3-hydroxy-3-methyl-butanoic acid.

Example 88trans-(R)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4,4-trifluoro-3-hydroxy-butyramide

The title compound, white solid (72 mg, 77%), MS (ISP) m/z=471.5[(M+H)⁺], mp 207° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and(R)-4,4,4-trifluoro-3-hydroxybutanoic acid.

Example 89 (S)-3-Hydroxy-pentanoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (66 mg, 77%), MS (ISP) m/z=431.4[(M+H)⁺], mp 158° C., was prepared in accordance with the general methodof example 2 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and (S)-methyl3-hydroxy-pentanoate.

Example 90trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-((1S,3S)-3-methoxy-cyclopentyl)-acetamide

The title compound, white solid (80 mg, 85%), MS (ISP) m/z=471.6[(M+H)⁺], mp 241° C., was prepared in accordance with the general methodof example 2 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and methyl2-((1S,3S)-3-methoxy-cyclopentyl)-acetate.

Example 91trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-((S)-4-hydroxy-tetrahydro-furan-2-yl)-acetamide

The title compound, off-white solid (14 mg, 15%), MS (ISP) m/z=459.5[(M+H)⁺], mp 155° C., was prepared in accordance with the general methodof example 2 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and ethyl2#45)-4-hydroxy-tetrahydrofuran-2-yl)-acetate.

Example 92trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-butyramide

The title compound, white solid (54 mg, 67%), MS (ISP) m/z=401.5[(M+H)⁺], mp 191° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and butyric acid.

Example 93 4-Methyl-pentanoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (72 mg, 84%), MS (ISP) m/z=429.5[(M+H)⁺], mp 182.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and4-methyl-pentanoic acid.

Example 94 Pentanoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (54 mg, 65%), MS (ISP) m/z=415.5[(M+H)⁺], mp 180.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and pentanoic acid.

Example 95trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4,4-trifluoro-butyramide

The title compound, white solid (53 mg, 58%), MS (ISP) m/z=455.4[(M+H)⁺], mp 195.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (88 mg, 0.2 mmol) and4,4,4-trifluoro-butanoic acid.

Example 96trans-N-(4-{2-[4-(6-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, white solid (101 mg, 88%), MS (ISP) m/z=385.4[(M+H)⁺], mp 207.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate D) (136 mg, 0.3 mmol) and acetic acid.

Example 97 trans-Tetrahydro-pyran-4-carboxylic acid(4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, off-white solid (128 mg, 94%), MS (ISP) m/z=455.4[(M+H)⁺], mp 219° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate D) (136 mg, 0.3 mmol) andtetrahydropyran-4-yl-carboxylic acid.

Example 98trans-N-(4-{2-[4-(6-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide

The title compound, off-white solid (131 mg, 93%), MS (ISP) m/z=469.5[(M+H)⁺], mp 212.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate D) (136 mg, 0.3 mmol) andtetrahydropyran-4-yl-acetic acid.

Example 99trans-3-Methoxy-N-(4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide

The title compound, white solid (100 mg, 78%), MS (ISP) m/z=429.4[(M+H)⁺], mp 158° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate D) (136 mg, 0.3 mmol) and3-methoxypropionic acid.

Example 100trans-N-(4-{2-[4-(6-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, white solid (96 mg, 83%), MS (ISP) m/z=387.4[(M+H)⁺], mp 217.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate E) (136 mg, 0.3 mmol) and acetic acid.

Example 101 Tetrahydro-pyran-4-carboxylic acidtrans-(4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (124 mg, 91%), MS (ISP) m/z=457.5[(M+H)⁺], mp 234.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate E) (136 mg, 0.3 mmol) andtetrahydropyran-4-yl-carboxylic acid.

Example 102trans-N-(4-{2-[4-(6-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide

The title compound, white solid (126 mg, 89%), MS (ISP) m/z=471.6[(M+H)⁺], mp 218.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate E) (136 mg, 0.3 mmol) andtetrahydropyran-4-yl-acetic acid.

Example 103trans-3-Methoxy-N-(4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide

The title compound, white solid (97 mg, 75%), MS (ISP) m/z=431.5[(M+H)⁺], mp 178.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate E) (136 mg, 0.3 mmol) and3-methoxypropionic acid.

Example 104trans-N-(4-{2-[4-(7-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, white solid (106 mg, 92%), MS (ISP) m/z=385.4[(M+H)⁺], mp 208° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate F) (136 mg, 0.3 mmol) and acetic acid.

Example 105 trans-Tetrahydro-pyran-4-carboxylic acid(4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (121 mg, 89%), MS (ISP) m/z=455.4[(M+H)⁺], mp 228° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate F) (136 mg, 0.3 mmol) andtetrahydropyran-4-yl-carboxylic acid.

Example 106trans-N-(4-{2-[4-(7-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide

The title compound, white solid (115 mg, 82%), MS (ISP) m/z=469.5[(M+H)⁺], mp 205.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate F) (136 mg, 0.3 mmol) andtetrahydropyran-4-yl-acetic acid.

Example 107trans-3-Methoxy-N-(4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide

The title compound, white solid (79 mg, 61%), MS (ISP) m/z=429.4[(M+H)⁺], mp 177° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate F) (136 mg, 0.3 mmol) and3-methoxypropionic acid.

Example 108trans-N-(4-{2-[4-(7-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, off-white solid (47 mg, 81%), MS (ISP) m/z=387.4[(M+H)⁺], mp 196.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and acetic acid.

Example 109 Tetrahydro-pyran-4-carboxylic acidtrans-(4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (60 mg, 88%), MS (ISP) m/z=457.5[(M+H)⁺], mp 223.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) andtetrahydropyran-4-yl-carboxylic acid.

Example 110trans-N-(4-{2-[4-(7-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide

The title compound, white solid (52 mg, 74%), MS (ISP) m/z=471.6[(M+H)⁺], mp 199° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) andtetrahydropyran-4-yl-acetic acid.

Example 111trans-3-Methoxy-N-(4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide

The title compound, off-white solid (53 mg, 82%), MS (ISP) m/z=431.6[(M+H)⁺], mp 163.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and3-methoxypropionic acid.

Example 112trans-(RS)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-2-hydroxy-propionamide

The title compound, light yellow solid (80 mg, 70%), MS (ISP) m/z=457.4[(M+H)⁺], mp 204° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylaminetrihydrochloride (intermediate E) (110 mg, 0.25 mmol) and(RS)-3,3,3-trifluoro-2-hydroxypropanoic acid.

Example 113trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide

The title compound, white solid (101 mg, 91%), MS (ISP) m/z=447.4[(M+H)⁺], mp 220° C., was prepared in accordance with the general methodof example 2 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl3,3-dimethoxy-propanoate.

Example 114trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4-dimethoxy-butyramide

The title compound, white solid (114 mg, 99%), MS (ISP) m/z=461.5[(M+H)⁺], mp 205.5° C., was prepared in accordance with the generalmethod of example 2 fromtrans-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl4,4-dimethoxy-butanoate.

Example 115 5-Methanesulfonyl-thiophene-2-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, off-white solid (98 mg, 76%), MS (ISP) m/z=519.2[(M+H)⁺], mp 229° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and5-methanesulfonyl-thiophene-2-carboxylic acid.

Example 116trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-6-methyl-nicotinamide

The title compound, white solid (100 mg, 89%), MS (ISP) m/z=450.4[(M+H)⁺], mp 201° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and6-methyl-nicotinic acid.

Example 117trans-4-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide

The title compound, off-white solid (110 mg, 96%), MS (ISP) m/z=460.5[(M+H)⁺], mp 243.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-cyano-benzoic acid.

Example 118trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-(4-methyl-piperazin-1-yl)-benzamide

The title compound, white solid (95 mg, 71%), MS (ISP) m/z=533.3[(M+H)⁺], mp 236° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-(4-methyl-piperazin-1-yl)-benzoic acid.

Example 119trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-6-morpholin-4-yl-nicotinamide

The title compound, white solid (108 mg, 83%), MS (ISP) m/z=521.5[(M+H)⁺], mp 222° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and6-morpholin-4-yl-nicotinic acid.

Example 120trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyridin-3-yl-benzamide

The title compound, white solid (110 mg, 86%), MS (ISP) m/z=512.5[(M+H)⁺], mp 218° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-pyridin-3-yl-benzoic acid.

Example 121 Benzo[1,3]dioxole-5-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (107 mg, 89%), MS (ISP) m/z=479.3[(M+H)⁺], mp 243.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andbenzo[1,3]dioxole-5-carboxylic acid.

Example 122trans-2-Benzo[1,3]dioxol-5-yl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, white solid (110 mg, 89%), MS (ISP) m/z=493.4[(M+H)⁺], mp 212° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and2-(benzo[1,3]dioxol-5-yl)-acetic acid.

Example 123 1-Hydroxy-cyclobutanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (81 mg, 76%), MS (ISP) m/z=429.4[(M+H)⁺], mp 177.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and1-hydroxy-cyclobutane-carboxylic acid.

Example 124trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-2-methyl-propionamide

The title compound, white solid (101 mg, 97%), MS (ISP) m/z=517.4[(M+H)⁺], mp 201° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and2-hydroxy-2-methyl-propionic acid.

Example 125trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-benzamide

The title compound, white solid (129 mg, 91%), MS (ISP) m/z=568.4[(M+H)⁺], mp 261.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-benzoic acid.

Example 126trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyrazol-1-yl-benzamide

The title compound, white solid (109 mg, 87%), MS (ISP) m/z=501.3[(M+H)⁺], mp 229° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-pyrazol-1-yl-benzoic acid.

Example 127trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzamide

The title compound, white solid (125 mg, 97%), MS (ISP) m/z=517.4[(M+H)⁺], mp 218° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid.

Example 128 Quinoline-6-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, off-white solid (120 mg, 99%), MS (ISP) m/z=486.4[(M+H)⁺], mp 227° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andquinoline-6-carboxylic acid.

Example 129 trans-2-Benzo[d]isoxazol-3-yl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, white solid (114 mg, 93%), MS (ISP) m/z=490.4[(M+H)⁺], mp 217.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and2-benzo[d]isoxazol-3-yl-acetic acid.

Example 130 5-Morpholin-4-yl-pyrazine-2-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (107 mg, 82%), MS (ISP) m/z=522.5[(M+H)⁺], mp 192.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and5-morpholin-4-yl-pyrazine-2-carboxylic acid.

Example 131trans-4-tert-Butyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide

The title compound, white solid (80 mg, 65%), MS (ISP) m/z=491.5[(M+H)⁺], mp 186.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-tert-butyl-benzoic acid.

Example 132trans-2,4-Dichloro-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide

The title compound, white solid (92 mg, 73%), MS (ISP) m/z=503.2[(M+H)⁺], mp 203.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and2,4-dichloro-benzoic acid.

Example 133trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyrrol-1-yl-benzamide

The title compound, white solid (72 mg, 58%), MS (ISP) m/z=500.4[(M+H)⁺], mp 234° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-pyrrol-1-yl-benzoic acid.

Example 134 Biphenyl-4-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (93 mg, 73%), MS (ISP) m/z=511.6[(M+H)⁺], mp 232° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andbiphenyl-4-carboxylic acid.

Example 135trans-(R)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-propionamide

The title compound, off-white solid (65 mg, 62%), MS (ISP) m/z=417.4[(M+H)⁺], mp 159° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and(R)-2-methoxy-propanoic acid.

Example 136trans-4-tert-Butoxy-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide

The title compound, white solid (82 mg, 65%), MS (ISP) m/z=507.3[(M+H)⁺], mp 200° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and4-tert-butoxy-benzoic acid.

Example 137trans-(S)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-propionamide

The title compound, white solid (63 mg, 61%), MS (ISP) m/z=417.4[(M+H)⁺], mp 158.5° C., was prepared in accordance with the generalmethod of example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and(S)-2-methoxy-propanoic acid.

Example 138trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzenesulfonamide

The title compound, light yellow solid (75 mg, 64%), MS (ISP) m/z=471.4[(M+H)⁺], mp 168.5° C., was prepared in accordance with the generalmethod of example 48 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) andbenzene-sulfonyl chloride.

Example 139trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide

The title compound, white solid (54 mg, 50%), MS (ISP) m/z=431.5[(M+H)⁺], mp 167° C., was prepared in accordance with the general methodof example 32 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and(RS)-3-methoxybutanoic acid.

Example 140 (R)-3-Hydroxy-pentanoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, white solid (58 mg, 54%), MS (ISP) m/z=431.5[(M+H)⁺], mp 161° C., was prepared in accordance with the general methodof example 2 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl(R)-3-hydroxy-pentanoate.

Example 141trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(1-hydroxy-cyclobutyl)-acetamide

The title compound, white solid (58 mg, 52%), MS (ISP) m/z=443.5[(M+H)⁺], mp 155° C., was prepared in accordance with the general methodof example 2 fromtrans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanaminetrihydrochloride (intermediate C) (110 mg, 0.25 mmol) and ethyl2-(1-hydroxy-cyclobutyl)-acetate.

Biochemical Assay

The ability of the compounds to bind to the 5-HT_(2A), D₃ and D₂receptors was determined using radioligand binding to cloned receptorsselectively expressed in HEK-293 EBNA cells.

Membrane Preparation

HEK293 EBNA cells were transiently transfected with expression plasmidsencoding for the human D₂ or D₃ or for the human 5-HT_(2A) receptor,respectively. The cells were harvested 48 h post-transfection, washedthree times with cold PBS and stored at −80° C. prior to use. The pelletwas suspended in cold 50 mM Tris-HCl buffer comprising 10 mM EDTA (pH7.4) and was homogenized with a Polytron (Kinematica AG, Basel,Switzerland) for 20-30 sec at 12.000 rpm. After centrifugation at48.000×g for 30 min at 4° C., the pellet was resuspended in cold 10 mMTris-HCl buffer comprising 0.1 mM EDTA (pH 7.4), homogenized, andcentrifuged as above. This pellet was further resuspended in a smallervolume of ice cold 10 mM Tris-HCl buffer comprising 0.1 mM EDTA (pH 7.4)and homogenized with a Polytron for 20-30 sec at 12.000 rpm. The proteincontent of this homogenate was determined with the Bio-Rad (Bradford)Protein Assay (Biorad Laboratories GmbH, München, Germany) according tothe instructions of the manufacturer using gamma globulin as thestandard. This homogenate was stored at −80° C. in aliquots and thawedimmediately prior to use.

Radioligand Binding Assay

Aliquots of membrane preparations were thawed at RT, resuspended inassay buffer (D₂, D₃: 50 mM Tris-HCl, 120 mM NaCl, 5 mM MgCl₂, 1 mMEDTA, 5 mM KCl, 1.5 mM CaCl₂, pH=7.4; 5-HT_(2A): 50 mM Tris-HCl, 10 mMMgCl₂, 1 mM EGTA, pH=7.4), homogenized with a Polytron for 20-30 sec at12.000 rpm and adjusted to a final concentration of approximately 7.5 μgprotein/well (D₂, D₃) and 15 μg protein/well (5-HT_(2A)), respectively.

The binding affinity (K_(i)) of the compounds was determined usingradioligand binding. Membranes were incubated in a total volume of 200μl with a fixed concentration of radioligand (final concentrationapproximately 0.7 nM [³H]-spiperone for D₂, 0.5 nM [³H]-spiperone forD₃, and 1.1 nM [³H]-ketanserin for 5-HT_(2A)) and ten concentrations oftest compound in ranging between 10 μM-0.1 nM for 1 h at RT. At the endof the incubation, the reaction mixtures were filtered on to unifilter96-well white microplates with bonded GF/C filters (Packard BioScience,Zürich, Switzerland; preincubated for 1 h in 0.1% polyethylenimine (PEI)in assay buffer) with a Filtermate 196 harvester (Packard BioScience)and washed 3 times with cold assay buffer. The nonspecific binding wasdetermined with equally composed reaction mixtures in the presence of 10μM unlabelled spiperone. Per well 45 μl of Microscint 40 (Perkin Elmer,Schwerzenbach, Switzerland) was added, plates for sealed, shaken for 20min and counted for 3 min on a Topcount Microplate Scintillation Counter(Can berra Packard SA, Zürich, Switzerland) with quenching correction.

Data Calculation

The CPM value for each duplicate of a concentration of competingcompound was averaged (y1), then the % specific binding was calculatedaccording to the equation (((y1−non-specific)/(totalbinding−non-specific))×100). Graphs were plotted with the % specificbinding using XLfit, a curve fitting program that iteratively plots thedata using Levenberg-Marquardt algorithm. The single site competitionanalysis equation used was y=A+((B−A)/(1+((x/C)D))), where y is the %specific binding, A is the minimum y, B is the maximum y, C is the IC₅₀,x is the log 10 of the concentration of the competing compound and D isthe slope of the curve (the Hill Coefficient). From these curves theIC₅₀ (inhibition concentration at which 50% specific binding of theradioligand was displaced) and Hill coefficient were determined. Theaffinity constant (K) was calculated using the Cheng-Prusoff equationK_(i)=(IC₅₀/1+([L]/K_(d)), where [L] is the concentration of radioligandand K_(d) is the dissociation constant of the radioligand at thereceptor as determined by the saturation isotherm.

The compounds of the present invention are selective dual modulators ofthe 5-HT_(2A) and D₃ receptors as is shown in table 1 below. Exampleswere tested in the above assay and found to have K_(i) 5-HT_(2A) valuesof about 0.1 nM to about 1 μM and K_(i) D₃ values of about 0.1 nM toabout 1 μM. Particular compounds of formula (I) were found to have K_(i)5-HT_(2A) values of about 1 nM to about 100 nM and K_(i) D₃ values ofabout 1 nM to about 200 nM. Most particular compounds of formula (I)were found to have K_(i) 5-HT_(2A) values of about 1 nM to about 25 nMand K_(i) D₃ values of about 1 nM to about 20 nM.

Particular compounds of formula (I) were found to bind more selectivelyto 5-HT_(2A) receptor than D₂ receptor by a factor of 5 or more, moreparticularly 10 or more, most particularly 25 or more. Particularcompounds of formula (I) were found to bind more selectively to D₃receptor than D₂ receptor by a factor of 5 or more, more particularly 10or more, most particularly 25 or more.

TABLE 1 Binding affinities to HEK293 EBNA cells expressing human (h)receptors of representative examples. D₂ D₃ 5-HT_(2a) Ex. K_(i) [nM]K_(i) [nM] K_(i) [nM] 1 486 18.3 9.1 2 802 28.8 6.4 3 1538 54.6 8.8 4780 11.8 6.5 5 1347 24 8.1 6 959 19.9 10.3 7 1360 43 5.6 8 1158 77.2 4.49 1463 32.7 5.6 10 683 30.3 6.1 11 515 55.7 2.9 12 996 150 7.4 13 26121.8 4.4 14 866 34.1 6.8 15 119 1.9 3.3 16 780 30.6 8.5 17 539 33 5.3 18163 1.6 2.6 19 305 1.9 3.5 20 302 3 2.5 21 271 3.6 3.7 22 220 3.2 2.2 23144 2.7 3 24 992 3.6 1.7 25 234 2.7 4.9 26 246 3 4.3 27 218 1.4 1.4 28392 6 4 29 461 23.2 5.3 30 265 4.3 2.9 31 217 4.3 2.9 32 770.1 12.7 22.933 503.5 38.2 5.9 34 869 24.9 20.1 35 1488 17.4 24.1 36 812.7 9.7 13.337 1471.4 19.6 9.7 38 1545.4 45.4 11 39 1018.3 9.8 16.1 40 1568 15.912.2 41 733.5 11.5 35.7 42 609.5 18.2 9.9 43 1044 120 6.3 44 481.2 7.667.63 45 341.9 10.7 11.1 46 289.2 13.25 14.8 47 871.2 57 18.8 48 1269.531.6 21.7 49 1093.5 22 17.6 50 240 6.72 39.4 51 586.8 5.07 13.7 52 55515.7 10.1 53 766.8 28.8 6.37 54 506.5 51.4 12.6 55 475 45.3 6.14 56 534044.3 19.2 57 867.1 16.9 4.52 58 592.9 27.1 5.92 59 702.5 7.74 15.7 60687.5 6.55 11 61 1124 18.7 11.8 62 547.5 10.7 3.62 63 485.6 18.5 11.1 641262.8 24.2 16.7 65 2451.9 24.1 14.9 66 781.5 24.9 11.5 67 1461 24.38.15 68 914.7 27.1 14.6 69 857.9 18.1 24.9 70 523.9 59.2 9.4 71 654.810.9 15.7 72 444.2 17 16.2 73 602.7 8.92 13.3 74 438.3 23.8 17.3 75705.1 16.6 10.2 76 709.4 25.4 13.2 77 754.6 12.1 11 78 322.5 92.8 28.779 773.3 47.3 19.2 80 198.4 15.4 16.2 81 945.4 12.9 22.8 82 425.6 17.212.2 83 837.2 28 23.5 84 1304.6 4.01 15.2 85 396.8 31.1 15.7 86 2562.737.6 23.9 87 999.7 21.6 25 88 731.8 19.7 33.1 89 887.4 20 30 90 1291.719.4 22.4 91 926.5 14.2 22.5 92 828.3 15.4 23.1 93 1277.1 22.7 24.6 941143.6 19.2 24.7 95 1253.7 20 29.6 96 248.8 4.64 75.2 97 274.6 14.2 25.598 640.6 9.45 75.9 99 429.7 4.8 86.9 100 915 7.58 215 101 1950 34.6 58.5102 1935 18.7 193.4 103 1486 11.8 255 104 1461 21.5 13.7 105 1126 72.75.67 106 2718 38 11.7 107 2471 30 12 108 2308 48.2 67.5 109 4510 98.719.7 110 2951 69.4 44 111 3564 46.8 37 112 842.6 37.9 11.4 113 1384.919.3 15.7 114 2365.4 68 18.1 115 516 33.8 9.46 116 312.6 52.1 15.5 117381.2 28 13 118 179.5 14.7 4.51 119 998.4 44.7 15.6 120 222.9 16.1 12.3121 3372 21.8 17.6 122 3042 18.6 33.7 123 958.6 131.2 9.8 124 1265 194.67.82 125 116.6 14.4 16.6 126 478 44.3 35.9 127 2147 19.5 48.9 128 500.620.5 23.2 129 1308.9 14.9 27.8 130 506 119.4 18.4 131 1663 146.7 66.7132 518.3 26.7 21.7 133 163.3 24.4 24.2 134 1132 18.6 23.4 135 680.5109.3 7 136 3161 69.5 41.4 137 788.5 252.5 20.1 138 242.6 15.5 70.5 139801.3 40.6 30.4 140 842.7 44.4 42 141 408.6 25.8 22.5

The invention claimed is:
 1. A compound of formula (I)

wherein X is O or S; Y is —C(O)— or —S(O)₂—; A is a single bond ordouble bond, with the proviso that when X is S then A is a double bond;R¹ is hydrogen, C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,cycloalkyl, heterocycloalkyl, aryl, aryl annellated to heterocycloalkyl,heteroaryl, or —N(R⁶)₂, wherein C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl are optionally substituted by one to threesubstituents selected independently from the group consisting of cyano,cycloalkyl, heterocycloalkyl, aryl, aryl annellated to heterocycloalkyl,heteroaryl, —C(O)N(R⁶)₂, —N(R⁶)₂, —NH(CO)—C₁₋₇ alkyl, hydroxy, C₁₋₇alkoxy, C₁₋₇ haloalkoxy, oxo, and —S(O)₂R⁷, and wherein cycloalkyl,heterocycloalkyl, aryl, aryl annellated to heterocycloalkyl andheteroaryl are optionally substituted by one to three independent R⁴; R²and R³ are each independently hydrogen, halogen, C₁₋₇ alkyl, C₁₋₇haloalkyl, hydroxy, C₁₋₇ alkoxy or C₁₋₇ haloalkoxy; R⁴ is halogen,cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, cycloalkyl, heterocycloalkyl, aryl,aryl annellated to heterocycloalkyl, heteroaryl, —C(O)N(R⁶)₂, —N(R⁶)₂,—NH(CO)—C₁₋₇ alkyl, hydroxy, C₁₋₇ alkoxy, C₁₋₇ haloalkoxy, oxo,—S(O)₂R⁷, or C₁₋₇ alkyl substituted by one to three substituentsselected independently from the group consisting of cyano, hydroxy, C₁₋₇alkoxy, and C₁₋₇ haloalkoxy, wherein cycloalkyl, heterocycloalkyl, aryl,and heteroaryl are optionally substituted by one to three independentR⁵; R⁵ is halogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, hydroxy, C₁₋₇alkoxy, C₁₋₇ haloalkoxy, or oxo; R⁶ is hydrogen or C₁₋₇ alkyl; R⁷ ishydrogen, C₁₋₇ alkyl, or aryl, wherein aryl is optionally substituted byone to three independent R⁵; or a pharmaceutically acceptable salt orester thereof.
 2. The compound of claim 1, wherein X is O and A is asingle bond.
 3. The compound of claim 1, wherein X is O and A is adouble bond.
 4. The compound of claim 1, wherein X is S and A is adouble bond.
 5. The compound of claim 2, wherein X is O, A is a singlebond and Y is —C(O)—.
 6. The compound of claim 1, wherein R¹ ishydrogen, C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,cycloalkyl, heterocycloalkyl, aryl, aryl annellated to heterocycloalkyl,heteroaryl, or —N(R⁶)₂, wherein C₁₋₇ alkyl, and C₁₋₇ haloalkyl areoptionally substituted by one to three substituents selectedindependently from the group consisting of cyano, cycloalkyl,heterocycloalkyl, aryl annellated to heterocycloalkyl, heteroaryl,—C(O)N(R⁶)₂, hydroxy, C₁₋₇ alkoxy, C₁₋₇ haloalkoxy, and —S(O)₂R⁷, andwherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl areoptionally substituted by one to three independent R⁴.
 7. The compoundof claim 1, wherein R¹ is methyl; methyl substituted by a substituentselected from the group consisting of cyano, cyclopropyl, cyclobutyl,hydroxy-cyclobutyl, methoxy-cyclopentyl, hydroxy-cyclohexyl,methoxy-cyclohexyl, oxetanyl, tetrahydrofuranyl,hydroxy-tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, benzodioxolyl,methyl-isoxazolyl, benzoisoxazolyl, hydroxy, methoxy, ethoxy, and—S(O)₂-methyl; ethyl; ethyl substituted with a substituent selected fromthe group consisting of hydroxy, methoxy, and C(O)—N(methyl)₂; n-propyl;n-propyl substituted by methoxy; iso-propyl; iso-propyl substituted byhydroxy; n-butyl; n-butyl substituted by hydroxy; iso-butyl; iso-butylsubstituted by hydroxy; tert-butyl; iso-pentyl; tert-pentyl;trifluoro-methyl; trifluoro-ethyl; trifluoro-ethyl substituted byhydroxy; trifluoro-n-propyl; trifluoro-n-propyl substituted by hydroxy;(E)-butenyl; iso-butenyl; propynyl; cyclopropyl; cyclopropyl substitutedby fluoro; cyclopropyl substituted by hydroxy; cyclobutyl; cyclobutylsubstituted by hydroxy; cyclohexyl; cyclohexyl substituted by methyl andhydroxy; tetrahydrofuranyl; tetrahydropyranyl; phenyl; phenylsubstituted by a substituent selected from the group consisting offluoro, chloro, cyano, methyl, tert-butyl, tert-butoxy, piperidinyl,methyl-piperazinyl, morpholinyl, dioxo-thiomorpholinyl, phenyl,pyrrolyl, pyrazolyl, methyl-oxadiazolyl, and pyridinyl; benzodioxolyl;thienyl; thienyl substituted by —S(O)₂-methyl; isoxazolyl;methyl-isoxazolyl; pyridinyl; methyl-pyridinyl; morpholinyl-pyridinyl;pyrazinyl; morpholinyl-pyrazinyl; or quinolinyl.
 8. The compound ofclaim 7, wherein R¹ is methyl; methyl substituted with a substituentselected from the group consisting of cyano, cyclopropyl, hydroxy,dioxanyl and —S(O)₂-methyl; ethyl; ethyl substituted with fluoro;iso-propyl, cyclopropyl; cyclobutyl; or tetrahydrofuranyl.
 9. Thecompound of claim 1, wherein R² is hydrogen.
 10. The compound of claim1, wherein R³ is hydrogen or methyl.
 11. The compound of claim 1,wherein R³ is hydrogen.
 12. The compound of claim 1, wherein R⁴ ishalogen, cyano, C₁₋₇ alkyl, C₁₋₇ haloalkyl, cycloalkyl,heterocycloalkyl, hydroxy, C₁₋₇ alkoxy, aryl, aryl annellated toheterocycloalkyl, heteroaryl or —S(O)₂R⁷, wherein cycloalkyl,heterocycloalkyl, aryl, aryl annellated to heterocycloalkyl andheteroaryl, are optionally substituted by one to three independent R⁵.13. The compound of claim 1, wherein R⁴ is fluoro, chloro, cyano,methyl, trifluoro-methyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl substituted by methoxy, cyclohexyl substituted by hydroxy ormethoxy, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl substitutedby oxo, dioxanyl, phenyl, benzodioxolyl, pyrrolyl, pyrazolyl,oxadiazolyl, methyl-oxadiazolyl, pyridinyl, hydroxy, methoxy, ethoxy,tert-butoxy, or —S(O)₂-methyl.
 14. The compound of claim 1, wherein R⁴is fluoro, cyano, cyclopropyl, dioxanyl, morpholinyl, phenyl, hydroxy,or —S(O)₂-methyl.
 15. The compound of claim 1, wherein R⁵ is halogen,hydroxy, C₁₋₇ alkyl, C₁₋₇ alkoxy, or oxo.
 16. The compound of claim 15,wherein R⁵ is fluoro, hydroxy, methyl, methoxy, or oxo.
 17. The compoundof claim 1, wherein R⁶ is C₁₋₇ alkyl.
 18. The compound of claim 1,wherein R⁶ is methyl.
 19. The compound of claim 1, wherein R⁷ is C₁₋₇alkyl.
 20. The compound of claim 19, wherein R⁷ is methyl.
 21. Thecompound of claim 1, selected from the group consisting of:N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-3-methoxy-cyclopentyl)-acetamide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-4-hydroxy-cyclohexyl)-acetamide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-methoxy-propionamide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-3-hydroxy-propionamide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-acetamide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-methoxy-acetamide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(trans-4-methoxy-cyclohexyl)-acetamide;andN-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-(tetrahydro-pyran-4-yl)-acetamideor a pharmaceutically acceptable salt or ester thereof.
 22. The compoundof claim 1, selected from the group consisting of:Tetrahydro-pyran-4-carboxylic acid{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;2-Ethoxy-N-{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;Cyclopropanecarboxylic acid{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;N-{trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamide;N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;Ethanesulfonic acid{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;N′-(trans-4{[4-(furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}cyclohexyl)-N,N-dimethylsulfamide;N-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;3-Methoxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-propionamide;and2-(trans-4-Methoxy-cyclohexyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamideor a pharmaceutically acceptable salt thereof.
 23. The compound of claim1, selected from the group consisting of:2-(trans-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;2-Methoxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;2-(Tetrahydro-pyran-4-yl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;Tetrahydro-pyran-4-carboxylic acid{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;2-((1R,3R)-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;2-((1S,3S)-3-Methoxy-cyclopentyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;2-Hydroxy-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;2-(trans-4-Hydroxy-cyclohexyl)-N-{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-acetamide;Quinoline-4-carboxylic acid{trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;andN-{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-methanesulfonamideor a pharmaceutically acceptable salt or ester thereof.
 24. The compoundof claim 1, selected from the group consisting of: Ethanesulfonic acid{trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-tetrahydro-2H-pyran-4-carboxamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-2H-pyran-4-yl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methoxypropanamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(rac-1,4-dioxan-2-yl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxyacetamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methylsulfonyl-acetamide;andtrans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-hydroxyacetamideor a pharmaceutically acceptable salt thereof.
 25. The compound of claim1, selected from the group consisting of:trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-hydroxypropanamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-3-carboxamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-2-carboxamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-fluoro-benzamide;trans-4-Chloro-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-trifluoromethyl-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide;Ethanesulfonic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;andtrans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-fluoro-benzenesulfonamideor a pharmaceutically acceptable salt thereof.
 26. The compound of claim1, selected from the group consisting of:trans-2-Cyclopropyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;Cyclobutanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;rac-Tetrahydro-pyran-3-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-4-Hydroxy-4-methyl-cyclohexanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;cis-4-Hydroxy-4-methyl-cyclohexanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide;1-Hydroxy-cyclopropanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-2-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;andtrans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-propionamideor a pharmaceutically acceptable salt or ester thereof.
 27. The compoundof claim 1, selected from the group consisting of:trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-[1,4]dioxan-2-yl-acetamide;Quinoline-4-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;Cyclopropanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-rac-(tetrahydro-furan-2-yl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-trans-(4-methoxy-cyclohexyl)-acetamide;N′-trans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-N,N-dimethyl-sulfamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(S)-[1,4]dioxan-2-yl-acetamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-(tetrahydro-furan-2-yl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(S)-(tetrahydro-furan-2-yl)-acetamide;andtrans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2,2-dimethyl-propionamideor a pharmaceutically acceptable salt thereof.
 28. The compound of claim1, selected from the group consisting of:trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methyl-butyramide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethyl-butyramide;trans-2-Cyclobutyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;trans-2,2-Difluoro-cyclopropanecarboxylic acid(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-isobutyramide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-2-methyl-butyramide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-oxetan-3-yl-acetamide;trans-3-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-1,1-dimethyl-urea;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2,2,2-trifluoro-acetamide;and 3-Methyl-but-2-enoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amideor a pharmaceutically acceptable salt thereof.
 29. The compound of claim1, selected from the group consisting of: (E)-Pent-3-enoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;But-2-ynoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-formamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(3-methyl-isoxazol-5-yl)-acetamide;3-Methyl-isoxazole-5-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-N′,N′-dimethyl-succinamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-3-methyl-butyramide;trans-(R)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4,4-trifluoro-3-hydroxy-butyramide;(S)-3-Hydroxy-pentanoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;andtrans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-((1S,3S)-3-methoxy-cyclopentyl)-acetamideor a pharmaceutically acceptable salt or ester thereof.
 30. The compoundof claim 1, selected from the group consisting of:trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-((S)-4-hydroxy-tetrahydro-furan-2-yl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-butyramide;4-Methyl-pentanoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;Pentanoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4,4-trifluoro-butyramide;trans-N-(4-{2-[4-(6-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;trans-Tetrahydro-pyran-4-carboxylic acid(4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(6-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide;trans-3-Methoxy-N-(4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;andtrans-N-(4-{2-[4-(6-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamideor a pharmaceutically acceptable salt thereof.
 31. The compound of claim1, selected from the group consisting of: Tetrahydro-pyran-4-carboxylicacidtrans-(4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(6-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide;trans-3-Methoxy-N-(4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;trans-N-(4-{2-[4-(7-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;trans-Tetrahydro-pyran-4-carboxylic acid(4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(7-Methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamide;trans-3-Methoxy-N-(4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;trans-N-(4-{2-[4-(7-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;Tetrahydro-pyran-4-carboxylic acidtrans-(4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;andtrans-N-(4-{2-[4-(7-Methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-4-yl)-acetamideor a pharmaceutically acceptable salt thereof.
 32. The compound of claim1, selected from the group consisting of:trans-3-Methoxy-N-(4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;trans-(RS)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-2-hydroxy-propionamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4,4-dimethoxy-butyramide;5-Methanesulfonyl-thiophene-2-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-6-methyl-nicotinamide;trans-4-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-(4-methyl-piperazin-1-yl)-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-6-morpholin-4-yl-nicotinamide;andtrans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyridin-3-yl-benzamideor a pharmaceutically acceptable salt thereof.
 33. The compound of claim1, selected from the group consisting of: Benzo[1,3]dioxole-5-carboxylicacidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-2-Benzo[1,3]dioxol-5-yl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;1-Hydroxy-cyclobutanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-2-methyl-propionamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyrazol-1-yl-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzamide;Quinoline-6-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-2-Benzo[d]isoxazol-3-yl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;and 5-Morpholin-4-yl-pyrazine-2-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amideor a pharmaceutically acceptable salt thereof.
 34. The compound of claim1, selected from the group consisting of:trans-4-tert-Butyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;trans-2,4-Dichloro-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-4-pyrrol-1-yl-benzamide;Biphenyl-4-carboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-(R)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-propionamide;trans-4-tert-Butoxy-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzamide;trans-(S)—N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-propionamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-benzenesulfonamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide;(R)-3-Hydroxy-pentanoic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amideandtrans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(1-hydroxy-cyclobutyl)-acetamide;or a pharmaceutically acceptable salt thereof.
 35. The compound of claim1, selected from the group consisting of:trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-propionamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(rac-1,4-dioxan-2-yl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methylsulfonyl-acetamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-hydroxyacetamide;trans-N-(4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-rac-tetrahydrofuran-3-carboxamide;trans-2-Cyclopropyl-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;Cyclobutanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;trans-2-Cyano-N-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-acetamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-propionamide;trans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-2-(R)-[1,4]dioxan-2-yl-acetamide;Cyclopropanecarboxylic acidtrans-(4-{2-[4-(2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amide;andtrans-N-(4-{2-[4-(2,3-Dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-isobutyramide;or a pharmaceutically acceptable salt thereof.
 36. A pharmaceuticalcomposition comprising a compound in accordance with claim 1 and apharmaceutically acceptable carrier.